G2Cdb::Human Disease report

Disease id
D00000093
Name
Acute myeloid leukaemia
Nervous system disease
no

Genes (5)

Gene Name/Description Mutations Found Literature Mutations Type Genetic association?
G00002000 MYO5A
myosin VA (heavy chain 12, myoxin)
Y (8643682) Translocation fusion (with another gene) (TF) Y
G00001624 PIK3CA
phosphoinositide-3-kinase, catalytic, alpha polypeptide
Y (16573740) No mutation found (N) N
G00001624 PIK3CA
phosphoinositide-3-kinase, catalytic, alpha polypeptide
Y (16764926) Microinsertion (MI) N
G00001624 PIK3CA
phosphoinositide-3-kinase, catalytic, alpha polypeptide
Y (16764926) Polymorphism (P) N
G00002011 MYH11
myosin, heavy chain 11, smooth muscle
Y (15041229) Translocation fusion (with another gene) (TF) N
G00002011 MYH11
myosin, heavy chain 11, smooth muscle
Y (15075086) Translocation fusion (with another gene) (TF) Y
G00002011 MYH11
myosin, heavy chain 11, smooth muscle
Y (15167911) Translocation fusion (with another gene) (TF) Y
G00002011 MYH11
myosin, heavy chain 11, smooth muscle
Y (15223639) Translocation fusion (with another gene) (TF) Y
G00002011 MYH11
myosin, heavy chain 11, smooth muscle
Y (15224374) Translocation fusion (with another gene) (TF) Y
G00002011 MYH11
myosin, heavy chain 11, smooth muscle
Y (15269306) Translocation fusion (with another gene) (TF) Y
G00002011 MYH11
myosin, heavy chain 11, smooth muscle
Y (15339697) Translocation fusion (with another gene) (TF) Y
G00002011 MYH11
myosin, heavy chain 11, smooth muscle
Y (15820957) Deletion (D) Y
G00002011 MYH11
myosin, heavy chain 11, smooth muscle
Y (16281071) Translocation fusion (with another gene) (TF) Y
G00002011 MYH11
myosin, heavy chain 11, smooth muscle
Y (16393682) Translocation fusion (with another gene) (TF) Y
G00002011 MYH11
myosin, heavy chain 11, smooth muscle
Y (16504290) Translocation fusion (with another gene) (TF) Y
G00002011 MYH11
myosin, heavy chain 11, smooth muscle
Y (17052753) Translocation fusion (with another gene) (TF) Y
G00002011 MYH11
myosin, heavy chain 11, smooth muscle
Y (17287858) Translocation fusion (with another gene) (TF) Y
G00002162 FUS
fused in sarcoma
Y (7533529) Translocation fusion (with another gene) (TF) Y
G00002162 FUS
fused in sarcoma
Y (7566973) Translocation fusion (with another gene) (TF) Y
G00002162 FUS
fused in sarcoma
Y (9242552) Translocation fusion (with another gene) (TF) Y
G00002162 FUS
fused in sarcoma
Y (9315104) Translocation fusion (with another gene) (TF) Y
G00002162 FUS
fused in sarcoma
Y (16303180) Translocation fusion (with another gene) (TF) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (12717436) Single nucleotide polymorphism (SNP) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (12717436) Microinsertion (MI) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (12717436) Trinucleotide substitution (TriNS) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (14982869) Microinsertion (MI) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (15009076) Unknown (?) N
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (15282682) No mutation found (N) N
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (15385933) Microinsertion (MI) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (15749679) Unknown (?) ?
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (15842656) Unknown (?) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (15929108) Unknown (?) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (17330262) Deletion (D) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (17330262) Translocation (T) Y

References

  • Mutations of the PTPN11 gene in therapy-related MDS and AML with rare balanced chromosome translocations.

    Christiansen DH, Desta F, Andersen MK and Pedersen-Bjergaard J

    Cytogenetic Laboratory, Section of Hematology/Oncology, Department of Clinical Genetics, The Juliane Marie Center, Copenhagen DK 2100 Ø, Denmark.

    Activating mutations of the PTPN11 gene encoding the SHP2 tyrosine phosphatase is the most common genetic abnormality in juvenile myelomonocytic leukemia and is sporadically observed in myelodysplasia (MDS) and acute myeloid leukemia (AML). An unselected series of 140 patients with therapy-related MDS or AML were investigated for mutations of PTPN11 in Exons 3, 4, 8, and 13. Four cases had mutations of the gene; three of these had deletions or loss of chromosome arm 7q. Two cases had rare balanced translocations to chromosome band 21q22 with rearrangement of the RUNX1 gene and the other two patients had rare balanced translocations to chromosome band 3q26 with rearrangement of the EVI1 gene. The findings support cooperation between so called Class I and Class II mutations in leukemogenesis.

    Genes, chromosomes & cancer 2007;46;6;517-21

  • Detection of the CBFB/MYH11 fusion gene in de novo acute myeloid leukemia (AML): a single-institution study of 224 Japanese AML patients.

    Monma F, Nishii K, Shiga J, Sugahara H, Lorenzo F, Watanabe Y, Kawakami K, Hosokai N, Yamamori S, Katayama N and Shiku H

    Division of Hematology and Oncology, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.

    The cytogenetic findings in acute myeloid leukemia (AML) are a powerful prognostic indicator. Among these abnormalities, the World Health Organization has classified inv(16)(p13q22), which is closely associated with the M4E classification in the French-American-British system, as indicating a good-risk AML. However, this chromosomal abnormality can often be difficult to detect. In this study, we used RT-PCR and FISH analysis to examine 224 Japanese adult de novo AML patients for the presence of the CBFB/MYH11 fusion transcript at the time of diagnosis. The CBFB/MYH11 fusion gene was detected in 17 patients (7.6%): eight patients had the inv(16) chromosome and in all of them it was M4E; nine patients did not have abnormalities in chromosome 16. AML with the CBFB/MYH11 fusion gene but without inv(16) was found in M2, M4, and M5, but not in M4E patients. There were no statistically significant differences in the clinical features of patients with the inv(16) and those with the cryptic inv(16) chromosome. These results indicate that even if eosinophilia is not found, molecular screening for CBFB/MYH11 fusion gene should be performed in all AML patients at the time of diagnosis to help guide disease management.

    Leukemia research 2007;31;4;471-6

  • Rare CBFB-MYH11 fusion transcripts in AML with inv(16)/t(16;16) are associated with therapy-related AML M4eo, atypical cytomorphology, atypical immunophenotype, atypical additional chromosomal rearrangements and low white blood cell count: a study on 162 patients.

    Schnittger S, Bacher U, Haferlach C, Kern W and Haferlach T

    MLL Munich Leukemia Laboratory, Munich, Germany. susanne.schnittger@mll-online.com

    The spectrum of CBFB-MYH11 fusion transcripts in acute myeloid leukemia (AML) M4eo with inv(16)/t(16;16) is heterogeneous. Approximately 85% show type A CBFB-MYH11 fusion transcripts. In addition, more than 10 different fusion transcripts have been reported. The prognostic impact and biological background of rare fusion transcripts remain open. In this study, a molecular characterization of CBFB-MYH11 transcripts in 162 patients with CBFB-MYH11 positive AML at diagnosis was performed. In total, 128 patients (79.0%) showed the fusion transcript type A, whereas nine different rare CBFB-MYH11 fusion genes were detected in 34 cases (21.0%). Rare fusion transcripts were found more frequently in therapy-related AML (P=0.0106). Numerical gains of the chromosomes 8, 21 and 22 were more frequently associated with type A (28.3%) than with rare fusions (12.9%) (P=0.012). Median white blood cell (WBC) count was higher in type A (35.4 G/l; range=1.1-279 G/l) than in cases with rare types (7.8 G/l; range=0.8-148.0 G/l) (P<0.0001). Rare fusion transcripts were correlated with an atypical cytomorphology not primarily suggestive for the FAB subtype M4eo (P=0.0203). Immunophenotype revealed lower CD2, CD13, CD33 and CD90 levels than in type A fusion cases (P=0.036, 0.002, 0.029 and 0.045, respectively). However, the type of fusion was not an independent prognostic parameter.

    Leukemia 2007;21;4;725-31

  • Rare mutations of the PIK3CA gene in malignancies of the hematopoietic system as well as endometrium, ovary, prostate and osteosarcomas, and discovery of a PIK3CA pseudogene.

    Müller CI, Miller CW, Hofmann WK, Gross ME, Walsh CS, Kawamata N, Luong QT and Koeffler HP

    Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA 90048, USA. mullerci@cshs.org

    Lipid kinase PIK3CA mutations have been described in several cancers. They clustered in two 'hot spots' located in helical (exon 9) and kinase (exon 20) domains associated with increased kinase activity strongly suggesting oncogenic potential. Mutational analysis of previously unexamined tumors showed an amino acid change from threonine to alanine (T1025A) in exon 20 in one of 28 endometrial cancer samples and 6 endometrial cell lines. Additionally, a silent polymorphism (T1025T) was found in two of 20 MDS samples, one of 43 NHL samples, two of 40 osteosarcoma samples and Ishikawa. The polymorphism was established by identifying two of 92 normal samples with the same change. No PIK3CA mutations were found in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and non-Hodgkin lymphomas (NHL) as well as in osteosarcomas, prostate and ovarian cancer samples. Additionally, a previously unidentified PIK3CA pseudogene spanning exons 9-13 on chromosome 22 was discovered.

    Leukemia research 2007;31;1;27-32

  • ELF4 is fused to ERG in a case of acute myeloid leukemia with a t(X;21)(q25-26;q22).

    Moore SD, Offor O, Ferry JA, Amrein PC, Morton CC and Dal Cin P

    Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.

    We report a novel chromosomal translocation in AML, t(X;21)(q25-26;q22), resulting in a fusion transcript between two ETS domain family members, ELF4 (at Xq25) and ERG (at 21q22). ERG has been associated previously with other fusion partners, specifically FUS and EWSR1, and implicated in both AML and Ewing's sarcoma. RT-PCR analysis of RNA isolated from bone marrow samples from the patient demonstrates that the translocation occurs within intron 1 of ERG isoform 1 (ERG-1) and intron 2 of ELF4 resulting in an in-frame fusion joining exon 2 from ELF4 with exon 2 of ERG. This is the first reported case of an ELF4-ERG fusion and identification of the specific ERG exon involved in the fusion that differentiates ERG isoforms. In addition, this case also directly implicates a new role for ELF4 in cancer.

    Funded by: NCI NIH HHS: P30 CA006516

    Leukemia research 2006;30;8;1037-42

  • Granulocytic sarcoma of mesentery in acute myeloid leukemia with CBFB/MYH11 fusion gene but not inv(16) chromosome: case report and review of literature.

    Fujieda A, Nishii K, Tamaru T, Otsuki S, Kobayashi K, Monma F, Ohishi K, Nakase K, Katayama N and Shiku H

    Division of Hematology and Oncology, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.

    Granulocytic sarcoma (GS) is a rare extra-medullary tumor and usually involves the skin, soft tissue, and lymph nodes. GS is found in 8% of acute myeloid leukemia (AML) patients, especially patients with t(8;21)AML. It has been suggested that GS is a poor prognostic factor in t(8;21)AML. Compared to t(8;21)AML, GS is rare in cases of inv(16)AML. Thus, the characteristics of inv(16) with GS are not well understood. Here, we describe a patient with AML and mesentery GS. The chromosomal analysis was normal, but molecular analysis detected the CBFB/MYH11 fusion gene in the blasts. A complete remission was achieved with standard induction therapy followed by high-dose cytarabine consolidation. We have also summarized 12 reported cases of inv(16)AML with GS and found that GS was commonly found in abdominal lesions. These observations suggest that when abdominal GS is diagnosed, an analysis of the CBFB/MYH11 fusion gene is necessary to make an appropriate decision regarding treatment options, even if no chromosomal abnormalities are found.

    Leukemia research 2006;30;8;1053-7

  • Absence of hot spot mutations of the PIK3CA gene in acute myeloid leukaemia.

    Hummerdal P, Andersson P, Willander K, Linderholm M, Söderkvist P and Jönsson JI

    European journal of haematology 2006;77;1;86-7

  • Coexistence of inversion 16 and the Philadelphia chromosome in acute and chronic myeloid leukemias : report of six cases and review of literature.

    Wu Y, Slovak ML, Snyder DS and Arber DA

    Division of Pathology, City of Hope National Medical Center, Duarte, CA, USA.

    We report 5 cases of chronic myelogenous leukemia (CML) and 1 case of acute myeloid leukemia (AML) with the dual presence of t(9;22) and inv(16). The 6 patients were 5 men and 1 woman with a median age of 42.5 years. All cases were BCR-ABL+ with p210 products detected in all CML cases and a p190 product detected in the AML case. An increase in bone marrow eosinophils was detected in 3 of 5 cases, and abnormal eosinophils were identified in these 3 cases. The CBFbeta-MYH11 fusion gene was confirmed in all 3 CML cases and the 1 AML case tested, and this correlated with the presence of abnormal eosinophils with coarse basophilic granules. Of 5 patients with CML, 4 had a rapid transformation to myeloid accelerated phase of blast crisis. The coexistence of t(9;22) and inv(16) in CML seems to correlate with more rapid transformation.

    American journal of clinical pathology 2006;125;2;260-6

  • Prognostic value of minimal residual disease (MRD) in acute myeloid leukemia (AML) with favorable cytogenetics [t(8;21) and inv(16)].

    Perea G, Lasa A, Aventín A, Domingo A, Villamor N, Queipo de Llano MP, Llorente A, Juncà J, Palacios C, Fernández C, Gallart M, Font L, Tormo M, Florensa L, Bargay J, Martí JM, Vivancos P, Torres P, Berlanga JJ, Badell I, Brunet S, Sierra J, Nomdedéu JF and Grupo Cooperativo para el Estudio y Tratamiento de las Leucemias Agudas y Miel

    Hematology Department, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.

    Most patients with acute myeloid leukemia (AML) and t(8;21) or inv(16) have a good prognosis with current anthracycline- and cytarabine-based protocols. Tandem analysis with flow cytometry (FC) and real-time RT-PCR (RQ-PCR) was applied to 55 patients, 28 harboring a t(8;21) and 27 an inv(16), including one case with a novel CBFbeta/MYH11 transcript. A total of 31% (n=17) of CR patients relapsed: seven with t(8;21) and 10 with inv(16). The mean amount of minimal residual disease (MRD) detected by FC in relapsed and nonrelapsed patients was markedly different: 0.3 vs 0.08% (P=0.002) at the end of treatment. The mean number of fusion transcript copies/ ABL x 10(4) also differed between relapsed and non-relapsed patients: 2385 vs 122 (P=0.001) after induction, 56 vs 7.6 after intensification (P=0.0001) and 75 vs 3.3 (P=0.0001) at the end of chemotherapy. Relapses were more common in patients with FC MRD level >0.1% at the end of treatment than in patients with < or = 0.1%: cumulative incidence of relapse (CIR) was 67 and 21% (P=0.03), respectively. Likewise, using RQ-PCR, a cutoff level of >10 copies at the end of treatment correlated with a high risk of relapse: CIR was 75% for patients with RQ-PCR >10 compared to 21% for patients with RQ-PCR levels < or = 10 (P=0.04). Combined use of FC and RQ-PCR may improve MRD detection, and provide useful clinical information on relapse kinetics in AML patients.

    Leukemia 2006;20;1;87-94

  • Acute myeloid leukemia in an adult Noonan syndrome patient with PTPN11 mutation.

    Matsubara K, Yabe H, Ogata T, Yoshida R and Fukaya T

    American journal of hematology 2005;79;2;171-2

  • Somatic PTPN11 mutations in childhood acute myeloid leukaemia.

    Tartaglia M, Martinelli S, Iavarone I, Cazzaniga G, Spinelli M, Giarin E, Petrangeli V, Carta C, Masetti R, Aricò M, Locatelli F, Basso G, Sorcini M, Pession A and Biondi A

    Dipartimento di Biologia cellulare e Neuroscienze, Istituto Superiore di Sanità, 299-00161 Rome, Italy. mtartaglia@iss.it

    Somatic mutations in PTPN11, the gene encoding the transducer SHP-2, have emerged as a novel class of lesions that upregulate RAS signalling and contribute to leukaemogenesis. In a recent study of 69 children and adolescents with de novo acute myeloid leukaemia (AML), we documented a non-random distribution of PTPN11 mutations among French-American-British (FAB) subtypes. Lesions were restricted to FAB-M5 cases, where they were relatively common (four of 12 cases). Here, we report on the results of a molecular screening performed on 181 additional unselected patients, enrolled in participating institutions of the Associazione Italiana Ematologia Oncologia Pediatrica-AML Study Group, to provide a more accurate picture of the prevalence, spectrum and distribution of PTPN11 mutations in childhood AML and to investigate their clinical relevance. We concluded that PTPN11 defects do not represent a frequent event in this heterogeneous group of malignancies (4.4%), although they recur in a considerable percentage of patients with FAB-M5 (18%). PTPN11 lesions rarely occur in other subtypes. Within the FAB-M5 group no clear association of PTPN11 mutations with any clinical variable was evident. Nearly two third of the patients with this subtype were found to harbour an activating mutation in PTPN11, NRAS, KRAS2 or FLT3.

    Funded by: Telethon: GGP04172

    British journal of haematology 2005;129;3;333-9

  • The incidence of submicroscopic deletions in reciprocal translocations is similar in acute myeloid leukemia, BCR-ABL positive acute lymphoblastic leukemia, and chronic myeloid leukemia.

    Bacher U, Schnittger S, Kern W, Hiddemann W, Haferlach T and Schoch C

    We compared the incidence of submicroscopic deletions accompanying balanced translocations using interphase fluorescence in situ hybridization (FISH) in 245 patients with chronic myeloid leukemia (CML), 79 patients with acute lymphoblastic leukemia (ALL) and BCR-ABL (n=70) or MLL rearrangements (n=29), and 412 patients with acute myeloid leukemia (AML) with CBFB-MYH11 (n=122), PML-RARalpha (n=108), AML1-ETO (n=112), or MLL rearrangements (n=98). The incidence of submicroscopic deletions was 2-9% depending on the entity.

    Haematologica 2005;90;4;558-9

  • Low frequency of exon 3 PTPN11 mutations in adult de novo acute myeloid leukemia. Analysis of a consecutive series of 173 patients.

    Nomdedéu J, Carricondo MT, Lasa A, Perea G, Aventin A and Sierra J

    A total of 173 samples obtained from adult patients with de novo acute myeloid leukemia (AML) were assayed for exon 3 PTPN11 mutations by single strand conformation polymorphism (SSCP) analysis and direct sequencing. Only three monocytic leukemias had point mutations (1.73%).

    Haematologica 2005;90;3;412-3

  • PTPN11 mutations in pediatric patients with acute myeloid leukemia: results from the Children's Cancer Group.

    Loh ML, Reynolds MG, Vattikuti S, Gerbing RB, Alonzo TA, Carlson E, Cheng JW, Lee CM, Lange BJ, Meshinchi S and Children's Cancer Group

    Department of Pediatrics, University of California, San Francisco, CA 94143, USA. lohm@itsa.ucsf.edu <lohm@itsa.ucsf.edu&gt;

    The PTPN11 gene encodes SHP-2, a nonreceptor protein tyrosine phosphatase that relays signals from activated growth factor receptors to p21(ras) (Ras) and other signaling molecules. Somatic PTPN11 mutations are common in patients with juvenile myelomonocytic leukemia (JMML) and have been reported in some other hematologic malignancies. We analyzed specimens from 278 pediatric patients with acute myelogenous leukemia (AML) who were enrolled on Children's Cancer Group trials 2941 and 2961 for PTPN11 mutations. Missense mutations of PTPN11 were detected in 11 (4%) of these samples. None of these patients had mutations in NRAS; however, one patient had evidence of a FLT3 alteration. Four of the patients with PTPN11 mutations (36%) were boys with French-American-British (FAB) morphology M5 AML (P=0.012). Patients with mutations also presented with elevated white blood cell counts. There was no difference in clinical outcome for patients with and without PTPN11 mutations. These characteristics identify a subset of pediatric AML with PTPN11 mutations that share clinical and biologic features with JMML.

    Funded by: NCI NIH HHS: K23 CA80915

    Leukemia 2004;18;11;1831-4

  • Multiplex real-time RT-PCR for prospective evaluation of WT1 and fusion gene transcripts in newly diagnosed de novo acute myeloid leukemia.

    Yanada M, Terakura S, Yokozawa T, Yamamoto K, Kiyoi H, Emi N, Kitamura K, Kohno A, Tanaka M, Tobita T, Takeo T, Sao H, Kataoka T, Kobayashi M, Takeshita A, Morishita Y, Naoe T and Sugiura I

    Department of Hematology, Nagoya University Graduate School of Medicine, Nagoya, Japan. myanada@med.nagoya-u.ac.jp

    Prognostic assessment is crucial for the management of AML. Although the use of karyotype analysis for risk-stratification is widely accepted, prognosis of AML remains ambiguous, particularly for patients categorized into the intermediate cytogenetic risk group and additional markers are required for an accurate prediction of outcome. For this study, we used multiplex real-time RT-PCR, which can simultaneously quantify WT1 and 10 distinct fusion gene transcripts, to prospectively evaluate the pre-treatment bone marrow findings of 53 de novo AML patients. Five patients with normal karyotype or insufficient metaphases detected by conventional karyotype analysis proved to have AML1-MTG8, CBFbeta-MYH11 or PML-RARalpha fusion transcripts. WT1 overexpression was observed in 92% of the patients, and the levels were significantly higher in the cytogenetic favorable risk group, especially patients with PML-RARalpha. WT1 levels also correlated with the percentage of blasts in bone marrow, especially in cases of core-binding factor leukemia. There was no association between initial WT1 levels and outcome in terms of event-free survival or overall survival. These results suggest that multiplex real-time RT-PCR is rapid and useful for the precise cytogenetic stratification of AML, and that WT1 levels at presentation correlate with several biologic features of leukemia, but have no prognostic significance.

    Leukemia & lymphoma 2004;45;9;1803-8

  • An inv(16)(p13q22) positive acute myeloid leukaemia relapsing as acute precursor B-cell lymphoblastic leukaemia.

    Boeckx N, van der Velden VH, Boogaerts M, Hagemeijer A, Vandenberghe P and van Dongen JJ

    Department of Laboratory Medicine, Laboratory of Haematology, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. nancy.boeckx@uz.kuleuven.ac.be

    We describe a case of a 38-year old male with inv(16)(p13q22) positive acute myeloid leukaemia (AML) with eosinophilia, relapsing after a molecular remission of almost three years. Remarkably, the leukaemia at relapse was identified as a precursor-B-cell acute lymphoblastic leukaemia (B-ALL) by cytology and immunophenotyping, but was inv(16)(p13q22) positive as revealed by interphase FISH, FICTION analysis, and real-time quantitative PCR. Analysis of immunoglobulin and T-cell receptor genes showed a bi-allelic DH2-JH rearrangement at relapse, but not at diagnosis. These findings indicate a myeloid to lymphoid lineage switch from an inv(16)(p13q22) positive leukaemia and show that IGH gene rearrangements can occur in the presence of CBFB-MYH11 fusion transcripts.

    Haematologica 2004;89;8;ECR28

  • Fluorescence in situ hybridization identifies cryptic t(16;16)(p13;q22) masked by del(16)(q22) in a case of AML-M4 Eo.

    Merchant SH, Haines S, Hall B, Hozier J and Viswanatha DS

    University of New Mexico Health Sciences Center, Department of Pathology, BRF Room 337C, 915 Camino de Salud, NE, Albuquerque, NM 87131. dviswanatha@salud.unm.edu

    We report a patient presenting with acute myeloid leukemia (AML)-M4 Eo, in whom conventional cytogenetic analysis revealed a 46, XY, del(16)(q22) karyotype. Molecular analysis of the bone marrow cells using reverse transcriptase polymerase chain reaction (RT-PCR) identified a CBFbeta-MYH11, "type A" fusion transcript. However, despite a thorough reevaluation, a balanced chromosome 16 abnormality could not be definitively identified by cytogenetics. Since there exists a small possibility of obtaining a false-positive PCR result, fluorescence in situ hybridization (FISH) analysis using dual-color, break-apart probes for CBFbeta was performed to elucidate the mechanism of fusion gene formation and thus confirm the RT-PCR results. FISH analysis clearly revealed a cryptic t(16;16), which was probably masked by the del(16)(q22). FISH is the preferred diagnostic procedure to elucidate the CBFbeta-MYH11 fusion in this situation, and resolves the possibility of both false-positive and false-negative results with RT-PCR technique. Due to the improved prognosis of AML associated with the CBFbeta-MYH11 fusion compared to AML generally, we recommend the use of FISH for detection of inv(16)/t(16;16)/CBFbeta-MYH11 in patients with failed, complex, or apparently normal cytogenetics, and in whom the cell morphology indicates the strong possibility of this gene fusion.

    The Journal of molecular diagnostics : JMD 2004;6;3;271-4

  • Mutations in PTPN11 are rare in adult myelodysplastic syndromes and acute myeloid leukemia.

    Watkins F, Fidler C, Boultwood J and Wainscoat JS

    American journal of hematology 2004;76;4;417

  • Genetic evidence for lineage-related and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia.

    Tartaglia M, Martinelli S, Cazzaniga G, Cordeddu V, Iavarone I, Spinelli M, Palmi C, Carta C, Pession A, Aricò M, Masera G, Basso G, Sorcini M, Gelb BD and Biondi A

    Dipartimento di Biologia cellulare e Neuroscienze, Istituto Superiore di Sanità, Viale Regina Elena, 299-00161 Rome, Italy. mtartaglia@iss.it

    SHP-2 is a protein tyrosine phosphatase functioning as signal transducer downstream to growth factor and cytokine receptors. SHP-2 is required during development, and germline mutations in PTPN11, the gene encoding SHP-2, cause Noonan syndrome. SHP-2 plays a crucial role in hematopoietic cell development. We recently demonstrated that somatic PTPN11 mutations are the most frequent lesion in juvenile myelomonocytic leukemia and are observed in a smaller percentage of children with other myeloid malignancies. Here, we report that PTPN11 lesions occur in childhood acute lymphoblastic leukemia (ALL). Mutations were observed in 23 of 317 B-cell precursor ALL cases, but not among 44 children with T-lineage ALL. In the former, lesions prevalently occurred in TEL-AML1(-) cases with CD19(+)/CD10(+)/cyIgM(-) immunophenotype. PTPN11, NRAS, and KRAS2 mutations were largely mutually exclusive and accounted for one third of common ALL cases. We also show that, among 69 children with acute myeloid leukemia, PTPN11 mutations occurred in 4 of 12 cases with acute monocytic leukemia (FAB-M5). Leukemia-associated PTPN11 mutations were missense and were predicted to result in SHP-2 gain-of-function. Our findings provide evidence for a wider role of PTPN11 lesions in leukemogenesis, but also suggest a lineage-related and differentiation stage-related contribution of these lesions to clonal expansion.

    Funded by: NHLBI NIH HHS: HL71207; NICHD NIH HHS: HD01294

    Blood 2004;104;2;307-13

  • Childhood acute myeloid leukemia with CBFbeta-MYH11 rearrangement: study of incidence, morphology, cytogenetics, and clinical outcomes of Chinese in Hong Kong.

    Chan NP, Wong WS, Ng MH, Tsang KS, Lau TT, Leung Y, Chik KW, Shing MM and Li CK

    Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China.

    We analyzed 43 consecutive cases of pediatric acute myeloid leukemia (AML) for the presence of the CBFbeta-MYH11 rearrangement using molecular techniques in a regional hospital in Hong Kong. Five cases (11.6%), 3 girls and 2 boys, ranging in age from 8 months to 14 years old, were found positive for the CBFbeta-MYH11 rearrangement. Morphologically, they were FAB M2 or M4 with or without eosinophilia (Eo). Typical M4Eo was observed in only one case. The molecular findings were in complete concordance with cytogenetic data, which revealed inv(16)(p13q22) in all and also gains of chromosome 4, 8, 22, and Y in one patient. Clinically, all 5 patients achieved complete remission after chemotherapy with favorable outcomes except for the patient with infantile AML, who relapsed 11 months after diagnosis, underwent cord blood transplantation, and was in second remission. This is the first clinicopathological study and documentation of the incidence of CBFbeta-MYH11 in childhood AML of Chinese in Hong Kong.

    American journal of hematology 2004;76;3;300-3

  • Translocation (11;13)(q23;q14) as the sole abnormality in a childhood de novo acute myelocytic leukemia.

    Tsang KS, Li CK, Lau TT, Wong AP, Leung Y and Ng MH

    Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Ngan Shing Street, Hong Kong, China. tsangks@cuhk.edu.hk

    We report a case of childhood de novo acute myelocytic leukemia (AML) with hyperleukocytosis with monoblastic features and deranged hemostasic function. G-band karyotyping demonstrated a previously unreported t(11;13)(q23;q14) in metaphase preparations from a fluorodeoxyuridine synchronized 1-day culture of leukophoresed cells. Multicolor fluorescence in situ hybridization revealed no cryptic rearrangements except for the translocation. Reverse transcriptase polymerase chain reaction showed no concomitant positivity of AML1/ETO, BCR/ABL, PML/RARA, and CBFbeta/MYH11 resulting from t(8;21)(q22;q22), t(9;22)(q34;q11), t(15;17)(q22;q11), and inv(16) (p13q22), respectively. This report of childhood de novo AML harboring t(11;13)(q23;q14) as the sole cytogenetic abnormality provides more data on the leukemogenesis of de novo AML with a 11q23 rearrangement.

    Cancer genetics and cytogenetics 2004;150;1;78-80

  • Molecular monitoring to identify a threshold of CBFbeta/MYH11 transcript below which continuous complete remission of acute myeloid leukemia inv16 is likely.

    Martinelli G, Rondoni M, Buonamici S, Ottaviani E, Piccaluga PP, Malagola M and Baccarani M

    Many patients with the inv(16) positive acute myeloid leukemia (AML) achieve complete remission (CR). Using real-time reverse transcriptase polymerase chain reaction (RT-PCR), we previously proposed critical CBFbeta-MYH11 transcript copy number thresholds to predict relapse or cure. We now update the molecular follow-up of our patients, also presenting the therapeutic management of these patients.

    Haematologica 2004;89;4;495-7

  • Mutations in PTPN11 are uncommon in adult myelodysplastic syndromes and acute myeloid leukaemia.

    Johan MF, Bowen DT, Frew ME, Goodeve AC, Wilson GA, Peake IR and Reilly JT

    British journal of haematology 2004;124;6;843-4

  • FLT3-activating mutations are associated with poor prognostic features in AML at diagnosis but they are not an independent prognostic factor.

    Chillón MC, Fernández C, García-Sanz R, Balanzategui A, Ramos F, Fernández-Calvo J, González M and Miguel JF

    Hematology Department, University Hospital of Salamanca, Salamanca, Spain.

    FLT3: gene alterations (internal tandem duplications - ITDs - and D835 mutations) are thought to be associated with poor-risk acute myeloid leukemia (AML). However, not all studies confirm this association, so it is still a matter of debate. Moreover, their association with other molecular abnormalities is less studied. We have investigated the presence of FLT3-ITD and D835 mutations in AML patients and their correlation with clinical and biological disease characteristics. The presence of ITD was analyzed in diagnostic samples of 176 AML patients and the D835 mutation in 135 of these patients. In all these patients, the presence of four well-known molecular abnormalities were also simultaneously characterized: PML/RARalpha, AML1/ETO, CBFbeta/MYH11 and MLL rearrangements. In all, 41 (23%) patients harbored FLT3 mutations, with 34 (19.3%) of them positive for the ITD, and seven (5%) positive for the D835 mutation. Of the acute promyelocytic leukemia (APL) patients, 16 (27%) showed FLT3 mutations, more frequently in M3 hypogranular cases (62% versus 17%, P=0.001) and cases with the short (bcr3) PML-RARalpha isoform (69%, P=0.002). In contrast, FLT3 was never altered in patients with inv(16), t(8;21) or 11q23 abnormalities. FLT3 mutations were significantly associated with some negative prognostic features at diagnosis (leukocytosis, high blast-cell percentage, and elevated LDH values), but they were not associated with different disease-free or overall survival. Therefore, we confirm a high frequency of FLT3 mutations in APL and in adult AML without recurrent cytogenetic translocations. In addition, they were not found as independent prognostic factors although associated with several adverse features at diagnosis.

    The hematology journal : the official journal of the European Haematology Association 2004;5;3;239-46

  • Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia.

    Tartaglia M, Niemeyer CM, Fragale A, Song X, Buechner J, Jung A, Hählen K, Hasle H, Licht JD and Gelb BD

    Department of Pediatrics, Mount Sinai School of Medicine, New York, New York, USA.

    We report here that individuals with Noonan syndrome and juvenile myelomonocytic leukemia (JMML) have germline mutations in PTPN11 and that somatic mutations in PTPN11 account for 34% of non-syndromic JMML. Furthermore, we found mutations in PTPN11 in a small percentage of individuals with myelodysplastic syndrome (MDS) and de novo acute myeloid leukemia (AML). Functional analyses documented that the two most common mutations in PTPN11 associated with JMML caused a gain of function.

    Nature genetics 2003;34;2;148-50

  • Characteristic sequence motifs at the breakpoints of the hybrid genes FUS/CHOP, EWS/CHOP and FUS/ERG in myxoid liposarcoma and acute myeloid leukemia.

    Panagopoulos I, Lassen C, Isaksson M, Mitelman F, Mandahl N and Aman P

    Department of Clinical Genetics, Lund University Hospital, Sweden.

    We have sequenced the breakpoint regions in one acute myeloid leukemia (AML) with t(16;21)(p11;q22) resulting in the formation of a FUS/ERG hybrid gene and in four myxoid liposarcomas (MLS), three of which had the translocation t(12;16) (q13;p11) and a FUS/CHOP fusion gene and one with t(12;22;20)(q13;q12;q11) and an EWS/CHOP hybrid gene. The breakpoints were localized to intron 7 of FUS, intron 1 of CHOP, an intronic sequence of ERG and intron 7 of EWS. In two MLS cases with t(12;16) and in the AML, the breaks in intron 7 of FUS had occurred close to each other, a few nucleotides downstream from a TG dinucleotide repeat region. The break in the two MLS had occurred in the same ATGGTG hexamer and in the AML 40 nucleotides upstream from the hexamer. The third case of t(12;16) MLS had a break upstream and near a TC-dinucleotide repeat region and a sequence similar to the chi bacterial recombination element was found to flank the breakpoint. In the MLS with the EWS/ CHOP hybrid gene, the break in intron 7 of EWS had occurred close to an Alu sequence. Similarly, in all 4 MLS, the breaks in intron 1 of CHOP were near an Alu sequence. No Alu or other repetitive sequences were found 250 bp upstream or downstream from the break in the ERG intron involved in the AML case. In the AML, the MLS with ESW/CHOP and in one MLS with FUS/CHOP there were one, two and six, respectively, nucleotide identity between the contributing germline sequences in the breakpoint. In the other two MLS cases, two and three extra nucleotides of unknown origin were inserted between the FUS and CHOP sequences. At the junction and/or in its close vicinity, identical oligomers, frequently containing a trinucleotide TGG, were found in both partner genes. Our data thus show that all four genes-FUS, EWS, CHOP and ERG-contain characteristic motifs in the breakpoint regions which may serve as specific recognition sites for DNA-binding proteins and have functional importance in the recombination events taking place between the chromosomes. Different sequence motifs may, however, play a role in each individual case.

    Oncogene 1997;15;11;1357-62

  • Consistent detection of TLS/FUS-ERG chimeric transcripts in acute myeloid leukemia with t(16;21)(p11;q22) and identification of a novel transcript.

    Kong XT, Ida K, Ichikawa H, Shimizu K, Ohki M, Maseki N, Kaneko Y, Sako M, Kobayashi Y, Tojou A, Miura I, Kakuda H, Funabiki T, Horibe K, Hamaguchi H, Akiyama Y, Bessho F, Yanagisawa M and Hayashi Y

    Department of Pediatrics, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Japan.

    16;21 translocation is a recurrent primary abnormality in acute myeloid leukemia (AML). The genes involved in this translocation are ERG on chromosome 21 and TLS/FUS on chromosome 16. The rearrangement of the two chromosomes forms the TLS/FUS-ERG fusion gene and produces a consistent chimeric transcript on the der (21) chromosome. In this study, we analyzed the clinical characteristics of 19 patients with t(16;21)-AML, including 2 patients who evolved from myelodysplastic syndrome, and detected the chimeric transcripts of the TLS/FUS-ERG fusion gene in the patients during various clinical stages by the reverse transcriptase-polymerase chain reaction (RT-PCR) technique. We found that the patients with t(16;21) are characterized by a relatively younger age (median age, 22 years old), involvement of various subtypes of French-American-British classification and a poor prognosis: 18 of the 19 patients died of the disease (median survival was 16 months). Four types of TLS/FUS-ERG chimeric transcripts including a novel type were noted in the RT-PCR analysis. The novel transcript contained an additional 138 nucleotides consisting of TLS/FUS exon 8 and ERG exons 7 and 8 and had an in-frame fusion. These chimeric transcripts were consistently detectable in the samples obtained not only at diagnosis and relapse but also in short and long complete remission, suggesting that t(16;21)-AML is resistant to conventional chemotherapy. Thus, we recommend that t(16;21) should be monitored by RT-PCR even in clinical remission and the patients should be treated by other more powerful modality like stem-cell transplantation in the first remission.

    Blood 1997;90;3;1192-9

  • Core binding factor beta-smooth muscle myosin heavy chain chimeric protein involved in acute myeloid leukemia forms unusual nuclear rod-like structures in transformed NIH 3T3 cells.

    Wijmenga C, Gregory PE, Hajra A, Schröck E, Ried T, Eils R, Liu PP and Collins FS

    Laboratory of Gene Transfer, National Center for Human Genome Research, Bethesda, MD 20892-4470, USA.

    Patients with the M4Eo subtype of acute myeloid leukemia almost invariably are found to have an inversion of chromosome 16 in their leukemic cells, which results in a gene fusion between the transcription factor called core binding factor beta (CBFbeta) on 16q and a smooth muscle myosin heavy chain (SMMHC) gene on 16p. Subcellular localizations of the wild-type CBFbeta and the CBFbeta-SMMHC fusion protein were determined by immunofluorescence of NIH 3T3 cells that overexpress wild-type or fusion protein. Normal CBFbeta showed an unexpected perinuclear pattern consistent with primary localization in the Golgi complex. The CBFbeta-SMMHC fusion protein had a very different pattern. Nuclear staining included rod-like crystalline structures as long as 11 microm. The heterodimeric partner of CBFbeta, CBFalpha, formed part of this complex. Cytoplasmic staining included stress fibers that colocalized with actin, probably as a consequence of the myosin heavy chain component of the fusion protein. Deletion of different regions of the CBFbeta portion of the fusion protein showed that binding to CBFalpha was not required for nuclear translocation. However, deletion of parts of the SMMHC domain of the fusion protein involved in myosin-mediated filament formation resulted in proteins that did not form rod-like structures. These observations confirm previous indirect evidence that the CBFbeta-SMMHC fusion protein is capable of forming macromolecular nuclear aggregates and suggests possible models for the mechanism of leukemic transformation.

    Proceedings of the National Academy of Sciences of the United States of America 1996;93;4;1630-5

  • Two distinct FUS breakpoint clusters in myxoid liposarcoma and acute myeloid leukemia with the translocations t(12;16) and t(16;21).

    Panagopoulos I, Mandahl N, Mitelman F and Aman P

    Department of Clinical Genetics, Lund University Hospital, Sweden.

    The FUS gene, which maps to 16p11, is fused to the CHOP gene in the t(12;16) (q13;p11) that characterizes myxoid liposarcomas (MLS) and to the ERG gene in acute myeloid leukemia (AML) with t(16;21) (p11;q22). In the present study we have mapped the breakpoints within FUS in 13 MLS with t(12;16) and in one AML with t(16;21). This region of FUS is about 3.9 kb and contains four exons. The breakpoints clustered to two zones (1 and 2). A strong association was found between the two known types of FUS/CHOP transcripts and the genomic localization of the breakpoints. In all cases expressing only type I or both type I and II FUS/CHOP transcript the genomic breakpoints mapped to zone 1. In all cases expressing only the type II transcript the breakpoints occurred in zone 2. The breakpoint in the AML case was in zone 1, suggesting that in-frame fusion transcripts are selected by similar mechanisms in both MLS and AML.

    Oncogene 1995;11;6;1133-7

  • Fusion of the FUS gene with ERG in acute myeloid leukemia with t(16;21)(p11;q22).

    Panagopoulos I, Aman P, Fioretos T, Höglund M, Johansson B, Mandahl N, Heim S, Behrendtz M and Mitelman F

    Department of Clinical Genetics, University Hospital, Lund, Sweden.

    It has been shown that the gene ERG in 21q22 is rearranged in the t(16;21)(p11;q22) associated with acute myeloid leukemia (AML). ERG is a member of the ETS gene family and is fused with EWS in a subset of Ewing's sarcomas. EWS in 22q12 has a very high homology with FUS (also called TLS) in 16p11; the latter gene is rearranged in the t(12;16)(q13;p11) that characterizes myxoid liposarcoma. To investigate whether FUS is involved in the t(16;21) of AML, we used the Southern blot technique and polymerase chain reaction (PCR) to examine the bone marrow of a 3-year-old boy with a t(16;21)(p11;q22)-positive AML. Hybridization of Southern blot filters containing digested DNA with probes for FUS and ERG showed both germline and aberrant fragments. Using specific primers for the 5' part of FUS and the 3' part of ERG, we amplified a 4.4 kb genomic FUS/ERG DNA fragment from the leukemic sample. In a second PCR experiment, in which we used primers upstream of the 5' part of ERG and downstream of the 3' part of FUS, a 5.6 kb fragment was amplified. Blotting and hybridization with specific probes for FUS and ERG revealed that the amplified fragments consisted of FUS/ERG and ERG/FUS hybrid DNA. Both PCR fragments, when used as probes, detected germline ERG and FUS as well as aberrant fragments on Southern blot filters. The results suggest that the t(16;21) in AML leads to rearrangement and fusion of the FUS and ERG genes.(ABSTRACT TRUNCATED AT 250 WORDS)

    Genes, chromosomes & cancer 1994;11;4;256-62

Literature (30)

Pubmed - human_disease

  • Detection of the CBFB/MYH11 fusion gene in de novo acute myeloid leukemia (AML): a single-institution study of 224 Japanese AML patients.

    Monma F, Nishii K, Shiga J, Sugahara H, Lorenzo F, Watanabe Y, Kawakami K, Hosokai N, Yamamori S, Katayama N and Shiku H

    Division of Hematology and Oncology, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.

    The cytogenetic findings in acute myeloid leukemia (AML) are a powerful prognostic indicator. Among these abnormalities, the World Health Organization has classified inv(16)(p13q22), which is closely associated with the M4E classification in the French-American-British system, as indicating a good-risk AML. However, this chromosomal abnormality can often be difficult to detect. In this study, we used RT-PCR and FISH analysis to examine 224 Japanese adult de novo AML patients for the presence of the CBFB/MYH11 fusion transcript at the time of diagnosis. The CBFB/MYH11 fusion gene was detected in 17 patients (7.6%): eight patients had the inv(16) chromosome and in all of them it was M4E; nine patients did not have abnormalities in chromosome 16. AML with the CBFB/MYH11 fusion gene but without inv(16) was found in M2, M4, and M5, but not in M4E patients. There were no statistically significant differences in the clinical features of patients with the inv(16) and those with the cryptic inv(16) chromosome. These results indicate that even if eosinophilia is not found, molecular screening for CBFB/MYH11 fusion gene should be performed in all AML patients at the time of diagnosis to help guide disease management.

    Leukemia research 2007;31;4;471-6

  • Rare CBFB-MYH11 fusion transcripts in AML with inv(16)/t(16;16) are associated with therapy-related AML M4eo, atypical cytomorphology, atypical immunophenotype, atypical additional chromosomal rearrangements and low white blood cell count: a study on 162 patients.

    Schnittger S, Bacher U, Haferlach C, Kern W and Haferlach T

    MLL Munich Leukemia Laboratory, Munich, Germany. susanne.schnittger@mll-online.com

    The spectrum of CBFB-MYH11 fusion transcripts in acute myeloid leukemia (AML) M4eo with inv(16)/t(16;16) is heterogeneous. Approximately 85% show type A CBFB-MYH11 fusion transcripts. In addition, more than 10 different fusion transcripts have been reported. The prognostic impact and biological background of rare fusion transcripts remain open. In this study, a molecular characterization of CBFB-MYH11 transcripts in 162 patients with CBFB-MYH11 positive AML at diagnosis was performed. In total, 128 patients (79.0%) showed the fusion transcript type A, whereas nine different rare CBFB-MYH11 fusion genes were detected in 34 cases (21.0%). Rare fusion transcripts were found more frequently in therapy-related AML (P=0.0106). Numerical gains of the chromosomes 8, 21 and 22 were more frequently associated with type A (28.3%) than with rare fusions (12.9%) (P=0.012). Median white blood cell (WBC) count was higher in type A (35.4 G/l; range=1.1-279 G/l) than in cases with rare types (7.8 G/l; range=0.8-148.0 G/l) (P<0.0001). Rare fusion transcripts were correlated with an atypical cytomorphology not primarily suggestive for the FAB subtype M4eo (P=0.0203). Immunophenotype revealed lower CD2, CD13, CD33 and CD90 levels than in type A fusion cases (P=0.036, 0.002, 0.029 and 0.045, respectively). However, the type of fusion was not an independent prognostic parameter.

    Leukemia 2007;21;4;725-31

  • ELF4 is fused to ERG in a case of acute myeloid leukemia with a t(X;21)(q25-26;q22).

    Moore SD, Offor O, Ferry JA, Amrein PC, Morton CC and Dal Cin P

    Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.

    We report a novel chromosomal translocation in AML, t(X;21)(q25-26;q22), resulting in a fusion transcript between two ETS domain family members, ELF4 (at Xq25) and ERG (at 21q22). ERG has been associated previously with other fusion partners, specifically FUS and EWSR1, and implicated in both AML and Ewing's sarcoma. RT-PCR analysis of RNA isolated from bone marrow samples from the patient demonstrates that the translocation occurs within intron 1 of ERG isoform 1 (ERG-1) and intron 2 of ELF4 resulting in an in-frame fusion joining exon 2 from ELF4 with exon 2 of ERG. This is the first reported case of an ELF4-ERG fusion and identification of the specific ERG exon involved in the fusion that differentiates ERG isoforms. In addition, this case also directly implicates a new role for ELF4 in cancer.

    Funded by: NCI NIH HHS: P30 CA006516

    Leukemia research 2006;30;8;1037-42

  • Granulocytic sarcoma of mesentery in acute myeloid leukemia with CBFB/MYH11 fusion gene but not inv(16) chromosome: case report and review of literature.

    Fujieda A, Nishii K, Tamaru T, Otsuki S, Kobayashi K, Monma F, Ohishi K, Nakase K, Katayama N and Shiku H

    Division of Hematology and Oncology, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.

    Granulocytic sarcoma (GS) is a rare extra-medullary tumor and usually involves the skin, soft tissue, and lymph nodes. GS is found in 8% of acute myeloid leukemia (AML) patients, especially patients with t(8;21)AML. It has been suggested that GS is a poor prognostic factor in t(8;21)AML. Compared to t(8;21)AML, GS is rare in cases of inv(16)AML. Thus, the characteristics of inv(16) with GS are not well understood. Here, we describe a patient with AML and mesentery GS. The chromosomal analysis was normal, but molecular analysis detected the CBFB/MYH11 fusion gene in the blasts. A complete remission was achieved with standard induction therapy followed by high-dose cytarabine consolidation. We have also summarized 12 reported cases of inv(16)AML with GS and found that GS was commonly found in abdominal lesions. These observations suggest that when abdominal GS is diagnosed, an analysis of the CBFB/MYH11 fusion gene is necessary to make an appropriate decision regarding treatment options, even if no chromosomal abnormalities are found.

    Leukemia research 2006;30;8;1053-7

  • Absence of hot spot mutations of the PIK3CA gene in acute myeloid leukaemia.

    Hummerdal P, Andersson P, Willander K, Linderholm M, Söderkvist P and Jönsson JI

    European journal of haematology 2006;77;1;86-7

  • Coexistence of inversion 16 and the Philadelphia chromosome in acute and chronic myeloid leukemias : report of six cases and review of literature.

    Wu Y, Slovak ML, Snyder DS and Arber DA

    Division of Pathology, City of Hope National Medical Center, Duarte, CA, USA.

    We report 5 cases of chronic myelogenous leukemia (CML) and 1 case of acute myeloid leukemia (AML) with the dual presence of t(9;22) and inv(16). The 6 patients were 5 men and 1 woman with a median age of 42.5 years. All cases were BCR-ABL+ with p210 products detected in all CML cases and a p190 product detected in the AML case. An increase in bone marrow eosinophils was detected in 3 of 5 cases, and abnormal eosinophils were identified in these 3 cases. The CBFbeta-MYH11 fusion gene was confirmed in all 3 CML cases and the 1 AML case tested, and this correlated with the presence of abnormal eosinophils with coarse basophilic granules. Of 5 patients with CML, 4 had a rapid transformation to myeloid accelerated phase of blast crisis. The coexistence of t(9;22) and inv(16) in CML seems to correlate with more rapid transformation.

    American journal of clinical pathology 2006;125;2;260-6

  • Prognostic value of minimal residual disease (MRD) in acute myeloid leukemia (AML) with favorable cytogenetics [t(8;21) and inv(16)].

    Perea G, Lasa A, Aventín A, Domingo A, Villamor N, Queipo de Llano MP, Llorente A, Juncà J, Palacios C, Fernández C, Gallart M, Font L, Tormo M, Florensa L, Bargay J, Martí JM, Vivancos P, Torres P, Berlanga JJ, Badell I, Brunet S, Sierra J, Nomdedéu JF and Grupo Cooperativo para el Estudio y Tratamiento de las Leucemias Agudas y Miel

    Hematology Department, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.

    Most patients with acute myeloid leukemia (AML) and t(8;21) or inv(16) have a good prognosis with current anthracycline- and cytarabine-based protocols. Tandem analysis with flow cytometry (FC) and real-time RT-PCR (RQ-PCR) was applied to 55 patients, 28 harboring a t(8;21) and 27 an inv(16), including one case with a novel CBFbeta/MYH11 transcript. A total of 31% (n=17) of CR patients relapsed: seven with t(8;21) and 10 with inv(16). The mean amount of minimal residual disease (MRD) detected by FC in relapsed and nonrelapsed patients was markedly different: 0.3 vs 0.08% (P=0.002) at the end of treatment. The mean number of fusion transcript copies/ ABL x 10(4) also differed between relapsed and non-relapsed patients: 2385 vs 122 (P=0.001) after induction, 56 vs 7.6 after intensification (P=0.0001) and 75 vs 3.3 (P=0.0001) at the end of chemotherapy. Relapses were more common in patients with FC MRD level >0.1% at the end of treatment than in patients with < or = 0.1%: cumulative incidence of relapse (CIR) was 67 and 21% (P=0.03), respectively. Likewise, using RQ-PCR, a cutoff level of >10 copies at the end of treatment correlated with a high risk of relapse: CIR was 75% for patients with RQ-PCR >10 compared to 21% for patients with RQ-PCR levels < or = 10 (P=0.04). Combined use of FC and RQ-PCR may improve MRD detection, and provide useful clinical information on relapse kinetics in AML patients.

    Leukemia 2006;20;1;87-94

  • Acute myeloid leukemia in an adult Noonan syndrome patient with PTPN11 mutation.

    Matsubara K, Yabe H, Ogata T, Yoshida R and Fukaya T

    American journal of hematology 2005;79;2;171-2

  • Somatic PTPN11 mutations in childhood acute myeloid leukaemia.

    Tartaglia M, Martinelli S, Iavarone I, Cazzaniga G, Spinelli M, Giarin E, Petrangeli V, Carta C, Masetti R, Aricò M, Locatelli F, Basso G, Sorcini M, Pession A and Biondi A

    Dipartimento di Biologia cellulare e Neuroscienze, Istituto Superiore di Sanità, 299-00161 Rome, Italy. mtartaglia@iss.it

    Somatic mutations in PTPN11, the gene encoding the transducer SHP-2, have emerged as a novel class of lesions that upregulate RAS signalling and contribute to leukaemogenesis. In a recent study of 69 children and adolescents with de novo acute myeloid leukaemia (AML), we documented a non-random distribution of PTPN11 mutations among French-American-British (FAB) subtypes. Lesions were restricted to FAB-M5 cases, where they were relatively common (four of 12 cases). Here, we report on the results of a molecular screening performed on 181 additional unselected patients, enrolled in participating institutions of the Associazione Italiana Ematologia Oncologia Pediatrica-AML Study Group, to provide a more accurate picture of the prevalence, spectrum and distribution of PTPN11 mutations in childhood AML and to investigate their clinical relevance. We concluded that PTPN11 defects do not represent a frequent event in this heterogeneous group of malignancies (4.4%), although they recur in a considerable percentage of patients with FAB-M5 (18%). PTPN11 lesions rarely occur in other subtypes. Within the FAB-M5 group no clear association of PTPN11 mutations with any clinical variable was evident. Nearly two third of the patients with this subtype were found to harbour an activating mutation in PTPN11, NRAS, KRAS2 or FLT3.

    Funded by: Telethon: GGP04172

    British journal of haematology 2005;129;3;333-9

  • The incidence of submicroscopic deletions in reciprocal translocations is similar in acute myeloid leukemia, BCR-ABL positive acute lymphoblastic leukemia, and chronic myeloid leukemia.

    Bacher U, Schnittger S, Kern W, Hiddemann W, Haferlach T and Schoch C

    We compared the incidence of submicroscopic deletions accompanying balanced translocations using interphase fluorescence in situ hybridization (FISH) in 245 patients with chronic myeloid leukemia (CML), 79 patients with acute lymphoblastic leukemia (ALL) and BCR-ABL (n=70) or MLL rearrangements (n=29), and 412 patients with acute myeloid leukemia (AML) with CBFB-MYH11 (n=122), PML-RARalpha (n=108), AML1-ETO (n=112), or MLL rearrangements (n=98). The incidence of submicroscopic deletions was 2-9% depending on the entity.

    Haematologica 2005;90;4;558-9

  • Low frequency of exon 3 PTPN11 mutations in adult de novo acute myeloid leukemia. Analysis of a consecutive series of 173 patients.

    Nomdedéu J, Carricondo MT, Lasa A, Perea G, Aventin A and Sierra J

    A total of 173 samples obtained from adult patients with de novo acute myeloid leukemia (AML) were assayed for exon 3 PTPN11 mutations by single strand conformation polymorphism (SSCP) analysis and direct sequencing. Only three monocytic leukemias had point mutations (1.73%).

    Haematologica 2005;90;3;412-3

  • Multiplex real-time RT-PCR for prospective evaluation of WT1 and fusion gene transcripts in newly diagnosed de novo acute myeloid leukemia.

    Yanada M, Terakura S, Yokozawa T, Yamamoto K, Kiyoi H, Emi N, Kitamura K, Kohno A, Tanaka M, Tobita T, Takeo T, Sao H, Kataoka T, Kobayashi M, Takeshita A, Morishita Y, Naoe T and Sugiura I

    Department of Hematology, Nagoya University Graduate School of Medicine, Nagoya, Japan. myanada@med.nagoya-u.ac.jp

    Prognostic assessment is crucial for the management of AML. Although the use of karyotype analysis for risk-stratification is widely accepted, prognosis of AML remains ambiguous, particularly for patients categorized into the intermediate cytogenetic risk group and additional markers are required for an accurate prediction of outcome. For this study, we used multiplex real-time RT-PCR, which can simultaneously quantify WT1 and 10 distinct fusion gene transcripts, to prospectively evaluate the pre-treatment bone marrow findings of 53 de novo AML patients. Five patients with normal karyotype or insufficient metaphases detected by conventional karyotype analysis proved to have AML1-MTG8, CBFbeta-MYH11 or PML-RARalpha fusion transcripts. WT1 overexpression was observed in 92% of the patients, and the levels were significantly higher in the cytogenetic favorable risk group, especially patients with PML-RARalpha. WT1 levels also correlated with the percentage of blasts in bone marrow, especially in cases of core-binding factor leukemia. There was no association between initial WT1 levels and outcome in terms of event-free survival or overall survival. These results suggest that multiplex real-time RT-PCR is rapid and useful for the precise cytogenetic stratification of AML, and that WT1 levels at presentation correlate with several biologic features of leukemia, but have no prognostic significance.

    Leukemia & lymphoma 2004;45;9;1803-8

  • An inv(16)(p13q22) positive acute myeloid leukaemia relapsing as acute precursor B-cell lymphoblastic leukaemia.

    Boeckx N, van der Velden VH, Boogaerts M, Hagemeijer A, Vandenberghe P and van Dongen JJ

    Department of Laboratory Medicine, Laboratory of Haematology, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. nancy.boeckx@uz.kuleuven.ac.be

    We describe a case of a 38-year old male with inv(16)(p13q22) positive acute myeloid leukaemia (AML) with eosinophilia, relapsing after a molecular remission of almost three years. Remarkably, the leukaemia at relapse was identified as a precursor-B-cell acute lymphoblastic leukaemia (B-ALL) by cytology and immunophenotyping, but was inv(16)(p13q22) positive as revealed by interphase FISH, FICTION analysis, and real-time quantitative PCR. Analysis of immunoglobulin and T-cell receptor genes showed a bi-allelic DH2-JH rearrangement at relapse, but not at diagnosis. These findings indicate a myeloid to lymphoid lineage switch from an inv(16)(p13q22) positive leukaemia and show that IGH gene rearrangements can occur in the presence of CBFB-MYH11 fusion transcripts.

    Haematologica 2004;89;8;ECR28

  • Fluorescence in situ hybridization identifies cryptic t(16;16)(p13;q22) masked by del(16)(q22) in a case of AML-M4 Eo.

    Merchant SH, Haines S, Hall B, Hozier J and Viswanatha DS

    University of New Mexico Health Sciences Center, Department of Pathology, BRF Room 337C, 915 Camino de Salud, NE, Albuquerque, NM 87131. dviswanatha@salud.unm.edu

    We report a patient presenting with acute myeloid leukemia (AML)-M4 Eo, in whom conventional cytogenetic analysis revealed a 46, XY, del(16)(q22) karyotype. Molecular analysis of the bone marrow cells using reverse transcriptase polymerase chain reaction (RT-PCR) identified a CBFbeta-MYH11, "type A" fusion transcript. However, despite a thorough reevaluation, a balanced chromosome 16 abnormality could not be definitively identified by cytogenetics. Since there exists a small possibility of obtaining a false-positive PCR result, fluorescence in situ hybridization (FISH) analysis using dual-color, break-apart probes for CBFbeta was performed to elucidate the mechanism of fusion gene formation and thus confirm the RT-PCR results. FISH analysis clearly revealed a cryptic t(16;16), which was probably masked by the del(16)(q22). FISH is the preferred diagnostic procedure to elucidate the CBFbeta-MYH11 fusion in this situation, and resolves the possibility of both false-positive and false-negative results with RT-PCR technique. Due to the improved prognosis of AML associated with the CBFbeta-MYH11 fusion compared to AML generally, we recommend the use of FISH for detection of inv(16)/t(16;16)/CBFbeta-MYH11 in patients with failed, complex, or apparently normal cytogenetics, and in whom the cell morphology indicates the strong possibility of this gene fusion.

    The Journal of molecular diagnostics : JMD 2004;6;3;271-4

  • Childhood acute myeloid leukemia with CBFbeta-MYH11 rearrangement: study of incidence, morphology, cytogenetics, and clinical outcomes of Chinese in Hong Kong.

    Chan NP, Wong WS, Ng MH, Tsang KS, Lau TT, Leung Y, Chik KW, Shing MM and Li CK

    Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China.

    We analyzed 43 consecutive cases of pediatric acute myeloid leukemia (AML) for the presence of the CBFbeta-MYH11 rearrangement using molecular techniques in a regional hospital in Hong Kong. Five cases (11.6%), 3 girls and 2 boys, ranging in age from 8 months to 14 years old, were found positive for the CBFbeta-MYH11 rearrangement. Morphologically, they were FAB M2 or M4 with or without eosinophilia (Eo). Typical M4Eo was observed in only one case. The molecular findings were in complete concordance with cytogenetic data, which revealed inv(16)(p13q22) in all and also gains of chromosome 4, 8, 22, and Y in one patient. Clinically, all 5 patients achieved complete remission after chemotherapy with favorable outcomes except for the patient with infantile AML, who relapsed 11 months after diagnosis, underwent cord blood transplantation, and was in second remission. This is the first clinicopathological study and documentation of the incidence of CBFbeta-MYH11 in childhood AML of Chinese in Hong Kong.

    American journal of hematology 2004;76;3;300-3

  • Translocation (11;13)(q23;q14) as the sole abnormality in a childhood de novo acute myelocytic leukemia.

    Tsang KS, Li CK, Lau TT, Wong AP, Leung Y and Ng MH

    Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Ngan Shing Street, Hong Kong, China. tsangks@cuhk.edu.hk

    We report a case of childhood de novo acute myelocytic leukemia (AML) with hyperleukocytosis with monoblastic features and deranged hemostasic function. G-band karyotyping demonstrated a previously unreported t(11;13)(q23;q14) in metaphase preparations from a fluorodeoxyuridine synchronized 1-day culture of leukophoresed cells. Multicolor fluorescence in situ hybridization revealed no cryptic rearrangements except for the translocation. Reverse transcriptase polymerase chain reaction showed no concomitant positivity of AML1/ETO, BCR/ABL, PML/RARA, and CBFbeta/MYH11 resulting from t(8;21)(q22;q22), t(9;22)(q34;q11), t(15;17)(q22;q11), and inv(16) (p13q22), respectively. This report of childhood de novo AML harboring t(11;13)(q23;q14) as the sole cytogenetic abnormality provides more data on the leukemogenesis of de novo AML with a 11q23 rearrangement.

    Cancer genetics and cytogenetics 2004;150;1;78-80

  • Molecular monitoring to identify a threshold of CBFbeta/MYH11 transcript below which continuous complete remission of acute myeloid leukemia inv16 is likely.

    Martinelli G, Rondoni M, Buonamici S, Ottaviani E, Piccaluga PP, Malagola M and Baccarani M

    Many patients with the inv(16) positive acute myeloid leukemia (AML) achieve complete remission (CR). Using real-time reverse transcriptase polymerase chain reaction (RT-PCR), we previously proposed critical CBFbeta-MYH11 transcript copy number thresholds to predict relapse or cure. We now update the molecular follow-up of our patients, also presenting the therapeutic management of these patients.

    Haematologica 2004;89;4;495-7

  • Mutations in PTPN11 are uncommon in adult myelodysplastic syndromes and acute myeloid leukaemia.

    Johan MF, Bowen DT, Frew ME, Goodeve AC, Wilson GA, Peake IR and Reilly JT

    British journal of haematology 2004;124;6;843-4

  • FLT3-activating mutations are associated with poor prognostic features in AML at diagnosis but they are not an independent prognostic factor.

    Chillón MC, Fernández C, García-Sanz R, Balanzategui A, Ramos F, Fernández-Calvo J, González M and Miguel JF

    Hematology Department, University Hospital of Salamanca, Salamanca, Spain.

    FLT3: gene alterations (internal tandem duplications - ITDs - and D835 mutations) are thought to be associated with poor-risk acute myeloid leukemia (AML). However, not all studies confirm this association, so it is still a matter of debate. Moreover, their association with other molecular abnormalities is less studied. We have investigated the presence of FLT3-ITD and D835 mutations in AML patients and their correlation with clinical and biological disease characteristics. The presence of ITD was analyzed in diagnostic samples of 176 AML patients and the D835 mutation in 135 of these patients. In all these patients, the presence of four well-known molecular abnormalities were also simultaneously characterized: PML/RARalpha, AML1/ETO, CBFbeta/MYH11 and MLL rearrangements. In all, 41 (23%) patients harbored FLT3 mutations, with 34 (19.3%) of them positive for the ITD, and seven (5%) positive for the D835 mutation. Of the acute promyelocytic leukemia (APL) patients, 16 (27%) showed FLT3 mutations, more frequently in M3 hypogranular cases (62% versus 17%, P=0.001) and cases with the short (bcr3) PML-RARalpha isoform (69%, P=0.002). In contrast, FLT3 was never altered in patients with inv(16), t(8;21) or 11q23 abnormalities. FLT3 mutations were significantly associated with some negative prognostic features at diagnosis (leukocytosis, high blast-cell percentage, and elevated LDH values), but they were not associated with different disease-free or overall survival. Therefore, we confirm a high frequency of FLT3 mutations in APL and in adult AML without recurrent cytogenetic translocations. In addition, they were not found as independent prognostic factors although associated with several adverse features at diagnosis.

    The hematology journal : the official journal of the European Haematology Association 2004;5;3;239-46

  • Characteristic sequence motifs at the breakpoints of the hybrid genes FUS/CHOP, EWS/CHOP and FUS/ERG in myxoid liposarcoma and acute myeloid leukemia.

    Panagopoulos I, Lassen C, Isaksson M, Mitelman F, Mandahl N and Aman P

    Department of Clinical Genetics, Lund University Hospital, Sweden.

    We have sequenced the breakpoint regions in one acute myeloid leukemia (AML) with t(16;21)(p11;q22) resulting in the formation of a FUS/ERG hybrid gene and in four myxoid liposarcomas (MLS), three of which had the translocation t(12;16) (q13;p11) and a FUS/CHOP fusion gene and one with t(12;22;20)(q13;q12;q11) and an EWS/CHOP hybrid gene. The breakpoints were localized to intron 7 of FUS, intron 1 of CHOP, an intronic sequence of ERG and intron 7 of EWS. In two MLS cases with t(12;16) and in the AML, the breaks in intron 7 of FUS had occurred close to each other, a few nucleotides downstream from a TG dinucleotide repeat region. The break in the two MLS had occurred in the same ATGGTG hexamer and in the AML 40 nucleotides upstream from the hexamer. The third case of t(12;16) MLS had a break upstream and near a TC-dinucleotide repeat region and a sequence similar to the chi bacterial recombination element was found to flank the breakpoint. In the MLS with the EWS/ CHOP hybrid gene, the break in intron 7 of EWS had occurred close to an Alu sequence. Similarly, in all 4 MLS, the breaks in intron 1 of CHOP were near an Alu sequence. No Alu or other repetitive sequences were found 250 bp upstream or downstream from the break in the ERG intron involved in the AML case. In the AML, the MLS with ESW/CHOP and in one MLS with FUS/CHOP there were one, two and six, respectively, nucleotide identity between the contributing germline sequences in the breakpoint. In the other two MLS cases, two and three extra nucleotides of unknown origin were inserted between the FUS and CHOP sequences. At the junction and/or in its close vicinity, identical oligomers, frequently containing a trinucleotide TGG, were found in both partner genes. Our data thus show that all four genes-FUS, EWS, CHOP and ERG-contain characteristic motifs in the breakpoint regions which may serve as specific recognition sites for DNA-binding proteins and have functional importance in the recombination events taking place between the chromosomes. Different sequence motifs may, however, play a role in each individual case.

    Oncogene 1997;15;11;1357-62

  • Consistent detection of TLS/FUS-ERG chimeric transcripts in acute myeloid leukemia with t(16;21)(p11;q22) and identification of a novel transcript.

    Kong XT, Ida K, Ichikawa H, Shimizu K, Ohki M, Maseki N, Kaneko Y, Sako M, Kobayashi Y, Tojou A, Miura I, Kakuda H, Funabiki T, Horibe K, Hamaguchi H, Akiyama Y, Bessho F, Yanagisawa M and Hayashi Y

    Department of Pediatrics, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Japan.

    16;21 translocation is a recurrent primary abnormality in acute myeloid leukemia (AML). The genes involved in this translocation are ERG on chromosome 21 and TLS/FUS on chromosome 16. The rearrangement of the two chromosomes forms the TLS/FUS-ERG fusion gene and produces a consistent chimeric transcript on the der (21) chromosome. In this study, we analyzed the clinical characteristics of 19 patients with t(16;21)-AML, including 2 patients who evolved from myelodysplastic syndrome, and detected the chimeric transcripts of the TLS/FUS-ERG fusion gene in the patients during various clinical stages by the reverse transcriptase-polymerase chain reaction (RT-PCR) technique. We found that the patients with t(16;21) are characterized by a relatively younger age (median age, 22 years old), involvement of various subtypes of French-American-British classification and a poor prognosis: 18 of the 19 patients died of the disease (median survival was 16 months). Four types of TLS/FUS-ERG chimeric transcripts including a novel type were noted in the RT-PCR analysis. The novel transcript contained an additional 138 nucleotides consisting of TLS/FUS exon 8 and ERG exons 7 and 8 and had an in-frame fusion. These chimeric transcripts were consistently detectable in the samples obtained not only at diagnosis and relapse but also in short and long complete remission, suggesting that t(16;21)-AML is resistant to conventional chemotherapy. Thus, we recommend that t(16;21) should be monitored by RT-PCR even in clinical remission and the patients should be treated by other more powerful modality like stem-cell transplantation in the first remission.

    Blood 1997;90;3;1192-9

  • Core binding factor beta-smooth muscle myosin heavy chain chimeric protein involved in acute myeloid leukemia forms unusual nuclear rod-like structures in transformed NIH 3T3 cells.

    Wijmenga C, Gregory PE, Hajra A, Schröck E, Ried T, Eils R, Liu PP and Collins FS

    Laboratory of Gene Transfer, National Center for Human Genome Research, Bethesda, MD 20892-4470, USA.

    Patients with the M4Eo subtype of acute myeloid leukemia almost invariably are found to have an inversion of chromosome 16 in their leukemic cells, which results in a gene fusion between the transcription factor called core binding factor beta (CBFbeta) on 16q and a smooth muscle myosin heavy chain (SMMHC) gene on 16p. Subcellular localizations of the wild-type CBFbeta and the CBFbeta-SMMHC fusion protein were determined by immunofluorescence of NIH 3T3 cells that overexpress wild-type or fusion protein. Normal CBFbeta showed an unexpected perinuclear pattern consistent with primary localization in the Golgi complex. The CBFbeta-SMMHC fusion protein had a very different pattern. Nuclear staining included rod-like crystalline structures as long as 11 microm. The heterodimeric partner of CBFbeta, CBFalpha, formed part of this complex. Cytoplasmic staining included stress fibers that colocalized with actin, probably as a consequence of the myosin heavy chain component of the fusion protein. Deletion of different regions of the CBFbeta portion of the fusion protein showed that binding to CBFalpha was not required for nuclear translocation. However, deletion of parts of the SMMHC domain of the fusion protein involved in myosin-mediated filament formation resulted in proteins that did not form rod-like structures. These observations confirm previous indirect evidence that the CBFbeta-SMMHC fusion protein is capable of forming macromolecular nuclear aggregates and suggests possible models for the mechanism of leukemic transformation.

    Proceedings of the National Academy of Sciences of the United States of America 1996;93;4;1630-5

  • Two distinct FUS breakpoint clusters in myxoid liposarcoma and acute myeloid leukemia with the translocations t(12;16) and t(16;21).

    Panagopoulos I, Mandahl N, Mitelman F and Aman P

    Department of Clinical Genetics, Lund University Hospital, Sweden.

    The FUS gene, which maps to 16p11, is fused to the CHOP gene in the t(12;16) (q13;p11) that characterizes myxoid liposarcomas (MLS) and to the ERG gene in acute myeloid leukemia (AML) with t(16;21) (p11;q22). In the present study we have mapped the breakpoints within FUS in 13 MLS with t(12;16) and in one AML with t(16;21). This region of FUS is about 3.9 kb and contains four exons. The breakpoints clustered to two zones (1 and 2). A strong association was found between the two known types of FUS/CHOP transcripts and the genomic localization of the breakpoints. In all cases expressing only type I or both type I and II FUS/CHOP transcript the genomic breakpoints mapped to zone 1. In all cases expressing only the type II transcript the breakpoints occurred in zone 2. The breakpoint in the AML case was in zone 1, suggesting that in-frame fusion transcripts are selected by similar mechanisms in both MLS and AML.

    Oncogene 1995;11;6;1133-7

  • Fusion of the FUS gene with ERG in acute myeloid leukemia with t(16;21)(p11;q22).

    Panagopoulos I, Aman P, Fioretos T, Höglund M, Johansson B, Mandahl N, Heim S, Behrendtz M and Mitelman F

    Department of Clinical Genetics, University Hospital, Lund, Sweden.

    It has been shown that the gene ERG in 21q22 is rearranged in the t(16;21)(p11;q22) associated with acute myeloid leukemia (AML). ERG is a member of the ETS gene family and is fused with EWS in a subset of Ewing's sarcomas. EWS in 22q12 has a very high homology with FUS (also called TLS) in 16p11; the latter gene is rearranged in the t(12;16)(q13;p11) that characterizes myxoid liposarcoma. To investigate whether FUS is involved in the t(16;21) of AML, we used the Southern blot technique and polymerase chain reaction (PCR) to examine the bone marrow of a 3-year-old boy with a t(16;21)(p11;q22)-positive AML. Hybridization of Southern blot filters containing digested DNA with probes for FUS and ERG showed both germline and aberrant fragments. Using specific primers for the 5' part of FUS and the 3' part of ERG, we amplified a 4.4 kb genomic FUS/ERG DNA fragment from the leukemic sample. In a second PCR experiment, in which we used primers upstream of the 5' part of ERG and downstream of the 3' part of FUS, a 5.6 kb fragment was amplified. Blotting and hybridization with specific probes for FUS and ERG revealed that the amplified fragments consisted of FUS/ERG and ERG/FUS hybrid DNA. Both PCR fragments, when used as probes, detected germline ERG and FUS as well as aberrant fragments on Southern blot filters. The results suggest that the t(16;21) in AML leads to rearrangement and fusion of the FUS and ERG genes.(ABSTRACT TRUNCATED AT 250 WORDS)

    Genes, chromosomes & cancer 1994;11;4;256-62

Pubmed - other

  • Mutations of the PTPN11 gene in therapy-related MDS and AML with rare balanced chromosome translocations.

    Christiansen DH, Desta F, Andersen MK and Pedersen-Bjergaard J

    Cytogenetic Laboratory, Section of Hematology/Oncology, Department of Clinical Genetics, The Juliane Marie Center, Copenhagen DK 2100 Ø, Denmark.

    Activating mutations of the PTPN11 gene encoding the SHP2 tyrosine phosphatase is the most common genetic abnormality in juvenile myelomonocytic leukemia and is sporadically observed in myelodysplasia (MDS) and acute myeloid leukemia (AML). An unselected series of 140 patients with therapy-related MDS or AML were investigated for mutations of PTPN11 in Exons 3, 4, 8, and 13. Four cases had mutations of the gene; three of these had deletions or loss of chromosome arm 7q. Two cases had rare balanced translocations to chromosome band 21q22 with rearrangement of the RUNX1 gene and the other two patients had rare balanced translocations to chromosome band 3q26 with rearrangement of the EVI1 gene. The findings support cooperation between so called Class I and Class II mutations in leukemogenesis.

    Genes, chromosomes & cancer 2007;46;6;517-21

  • Rare mutations of the PIK3CA gene in malignancies of the hematopoietic system as well as endometrium, ovary, prostate and osteosarcomas, and discovery of a PIK3CA pseudogene.

    Müller CI, Miller CW, Hofmann WK, Gross ME, Walsh CS, Kawamata N, Luong QT and Koeffler HP

    Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA 90048, USA. mullerci@cshs.org

    Lipid kinase PIK3CA mutations have been described in several cancers. They clustered in two 'hot spots' located in helical (exon 9) and kinase (exon 20) domains associated with increased kinase activity strongly suggesting oncogenic potential. Mutational analysis of previously unexamined tumors showed an amino acid change from threonine to alanine (T1025A) in exon 20 in one of 28 endometrial cancer samples and 6 endometrial cell lines. Additionally, a silent polymorphism (T1025T) was found in two of 20 MDS samples, one of 43 NHL samples, two of 40 osteosarcoma samples and Ishikawa. The polymorphism was established by identifying two of 92 normal samples with the same change. No PIK3CA mutations were found in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and non-Hodgkin lymphomas (NHL) as well as in osteosarcomas, prostate and ovarian cancer samples. Additionally, a previously unidentified PIK3CA pseudogene spanning exons 9-13 on chromosome 22 was discovered.

    Leukemia research 2007;31;1;27-32

  • PTPN11 mutations in pediatric patients with acute myeloid leukemia: results from the Children's Cancer Group.

    Loh ML, Reynolds MG, Vattikuti S, Gerbing RB, Alonzo TA, Carlson E, Cheng JW, Lee CM, Lange BJ, Meshinchi S and Children's Cancer Group

    Department of Pediatrics, University of California, San Francisco, CA 94143, USA. lohm@itsa.ucsf.edu <lohm@itsa.ucsf.edu&gt;

    The PTPN11 gene encodes SHP-2, a nonreceptor protein tyrosine phosphatase that relays signals from activated growth factor receptors to p21(ras) (Ras) and other signaling molecules. Somatic PTPN11 mutations are common in patients with juvenile myelomonocytic leukemia (JMML) and have been reported in some other hematologic malignancies. We analyzed specimens from 278 pediatric patients with acute myelogenous leukemia (AML) who were enrolled on Children's Cancer Group trials 2941 and 2961 for PTPN11 mutations. Missense mutations of PTPN11 were detected in 11 (4%) of these samples. None of these patients had mutations in NRAS; however, one patient had evidence of a FLT3 alteration. Four of the patients with PTPN11 mutations (36%) were boys with French-American-British (FAB) morphology M5 AML (P=0.012). Patients with mutations also presented with elevated white blood cell counts. There was no difference in clinical outcome for patients with and without PTPN11 mutations. These characteristics identify a subset of pediatric AML with PTPN11 mutations that share clinical and biologic features with JMML.

    Funded by: NCI NIH HHS: K23 CA80915

    Leukemia 2004;18;11;1831-4

  • Mutations in PTPN11 are rare in adult myelodysplastic syndromes and acute myeloid leukemia.

    Watkins F, Fidler C, Boultwood J and Wainscoat JS

    American journal of hematology 2004;76;4;417

  • Genetic evidence for lineage-related and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia.

    Tartaglia M, Martinelli S, Cazzaniga G, Cordeddu V, Iavarone I, Spinelli M, Palmi C, Carta C, Pession A, Aricò M, Masera G, Basso G, Sorcini M, Gelb BD and Biondi A

    Dipartimento di Biologia cellulare e Neuroscienze, Istituto Superiore di Sanità, Viale Regina Elena, 299-00161 Rome, Italy. mtartaglia@iss.it

    SHP-2 is a protein tyrosine phosphatase functioning as signal transducer downstream to growth factor and cytokine receptors. SHP-2 is required during development, and germline mutations in PTPN11, the gene encoding SHP-2, cause Noonan syndrome. SHP-2 plays a crucial role in hematopoietic cell development. We recently demonstrated that somatic PTPN11 mutations are the most frequent lesion in juvenile myelomonocytic leukemia and are observed in a smaller percentage of children with other myeloid malignancies. Here, we report that PTPN11 lesions occur in childhood acute lymphoblastic leukemia (ALL). Mutations were observed in 23 of 317 B-cell precursor ALL cases, but not among 44 children with T-lineage ALL. In the former, lesions prevalently occurred in TEL-AML1(-) cases with CD19(+)/CD10(+)/cyIgM(-) immunophenotype. PTPN11, NRAS, and KRAS2 mutations were largely mutually exclusive and accounted for one third of common ALL cases. We also show that, among 69 children with acute myeloid leukemia, PTPN11 mutations occurred in 4 of 12 cases with acute monocytic leukemia (FAB-M5). Leukemia-associated PTPN11 mutations were missense and were predicted to result in SHP-2 gain-of-function. Our findings provide evidence for a wider role of PTPN11 lesions in leukemogenesis, but also suggest a lineage-related and differentiation stage-related contribution of these lesions to clonal expansion.

    Funded by: NHLBI NIH HHS: HL71207; NICHD NIH HHS: HD01294

    Blood 2004;104;2;307-13

  • Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia.

    Tartaglia M, Niemeyer CM, Fragale A, Song X, Buechner J, Jung A, Hählen K, Hasle H, Licht JD and Gelb BD

    Department of Pediatrics, Mount Sinai School of Medicine, New York, New York, USA.

    We report here that individuals with Noonan syndrome and juvenile myelomonocytic leukemia (JMML) have germline mutations in PTPN11 and that somatic mutations in PTPN11 account for 34% of non-syndromic JMML. Furthermore, we found mutations in PTPN11 in a small percentage of individuals with myelodysplastic syndrome (MDS) and de novo acute myeloid leukemia (AML). Functional analyses documented that the two most common mutations in PTPN11 associated with JMML caused a gain of function.

    Nature genetics 2003;34;2;148-50

© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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