G2Cdb::Human Disease report

Disease id
D00000099
Name
Juvenile myelomonocytic leukaemia
Nervous system disease
no

Genes (2)

Gene Name/Description Mutations Found Literature Mutations Type Genetic association?
G00000036 NF1
neurofibromin 1
Y (9639526) Unknown (?) Y
G00000036 NF1
neurofibromin 1
Y (17353900) Single nucleotide polymorphism (SNP) 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 (14644997) Microinsertion (MI) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (15085150) Single nucleotide polymorphism (SNP) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (15211660) Deletion (D) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (15539800) Microinsertion (MI) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (15928039) Microinsertion (MI) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (16188759) Unknown (?) Y

References

  • Genome-wide single-nucleotide polymorphism analysis in juvenile myelomonocytic leukemia identifies uniparental disomy surrounding the NF1 locus in cases associated with neurofibromatosis but not in cases with mutant RAS or PTPN11.

    Flotho C, Steinemann D, Mullighan CG, Neale G, Mayer K, Kratz CP, Schlegelberger B, Downing JR and Niemeyer CM

    Division of Pediatric Hematology-Oncology, University of Freiburg, Freiburg, Germany. christian.flotho@uniklinik-freiburg.de

    Juvenile myelomonocytic leukemia (JMML) is a malignant hematopoietic disorder whose proliferative component is a result of RAS pathway deregulation caused by somatic mutation in the RAS or PTPN11 oncogenes or in patients with underlying neurofibromatosis type 1 (NF-1), by loss of NF1 gene function. To search for potential collaborating genetic abnormalities, we used oligonucleotide arrays to analyse over 116 000 single-nucleotide polymorphisms across the genome in 16 JMML samples with normal karyotype. Evaluation of the SNP genotypes identified large regions of homozygosity on chromosome 17q, including the NF1 locus, in four of the five samples from patients with JMML and NF-1. The homozygous region was at least 55 million base pairs in each case. The genomic copy number was normal within the homozygous region, indicating uniparental disomy (UPD). In contrast, the array data provided no evidence for 17q UPD in any of the 11 JMML cases without NF-1. We used array-based comparative genomic hybridization to confirm 17q disomy, and microsatellite analysis was performed to verify homozygosity. Mutational analysis demonstrated that the inactivating NF1 lesion was present on both alleles in each case. In summary, our data indicate that a mitotic recombination event in a JMML-initiating cell led to 17q UPD with homozygous loss of normal NF1, provide confirmatory evidence that the NF1 gene is crucial for the increased incidence of JMML in NF-1 patients, and corroborate the concept that RAS pathway deregulation is central to JMML pathogenesis.

    Oncogene 2007;26;39;5816-21

  • The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease.

    Kratz CP, Niemeyer CM, Castleberry RP, Cetin M, Bergsträsser E, Emanuel PD, Hasle H, Kardos G, Klein C, Kojima S, Stary J, Trebo M, Zecca M, Gelb BD, Tartaglia M and Loh ML

    University of California, Room HSE-302 Box 0519, San Francisco, CA 94143, USA.

    Germ line PTPN11 mutations cause 50% of cases of Noonan syndrome (NS). Somatic mutations in PTPN11 occur in 35% of patients with de novo, nonsyndromic juvenile myelomonocytic leukemia (JMML). Myeloproliferative disorders (MPDs), either transient or more fulminant forms, can also occur in infants with NS (NS/MPD). We identified PTPN11 mutations in blood or bone marrow specimens from 77 newly reported patients with JMML (n = 69) or NS/MPD (n = 8). Together with previous reports, we compared the spectrum of PTPN11 mutations in 3 groups: (1) patients with JMML (n = 107); (2) patients with NS/MPD (n = 19); and (3) patients with NS (n = 243). Glu76 was the most commonly affected residue in JMML (n = 45), with the Glu76Lys alteration (n = 29) being most frequent. Eight of 19 patients with NS/MPD carried the Thr73Ile substitution. These data suggest that there is a genotype/phenotype correlation in the spectrum of PTPN11 mutations found in patients with JMML, NS/MPD, and NS. This supports the need to characterize the spectrum of hematologic abnormalities in individuals with NS and to better define the impact of the PTPN11 lesion on the disease course in patients with NS/MPD and JMML.

    Funded by: NCI NIH HHS: K24 CA80916, P30 CA82103, R01 CA104282, R01 CA95621; NHLBI NIH HHS: HL074728, HL71207; NICHD NIH HHS: HD01294; Telethon: GGP04172

    Blood 2005;106;6;2183-5

  • A new PTPN11 mutation in juvenile myelomonocytic leukaemia associated with Noonan syndrome.

    Giovannini L, Cavé H, Ferrero-Vacher C, Boutte P and Sirvent N

    Acta paediatrica (Oslo, Norway : 1992) 2005;94;5;636-7

  • A 3-bp deletion mutation of PTPN11 in an infant with severe Noonan syndrome including hydrops fetalis and juvenile myelomonocytic leukemia.

    Yoshida R, Miyata M, Nagai T, Yamazaki T and Ogata T

    Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development, 3-35-31 Taishido, Setagaya, Tokyo 154-8567, Japan.

    A de novo 3-bp deletion (179-181delGTG) was identified at exon 3 of the PTPN11 gene in a female infant with severe Noonan phenotype including hydrops fetalis and juvenile myelomonocytic leukemia. Since the 3-bp deletion is predicted to result in loss of the 60th glycine in the N-SH2 domain that is directly involved in the intramolecular interaction between the N-SH2 and the PTP domains of the PTPN11 protein, this mutation would disrupt the N-SH2/PTP binding in the absence of a phosphopeptide, leading to an excessive phosphatase activity. The results expand the spectrum of PTPN11 mutations in Noonan syndrome (NS), and suggest that a PTPN11 mutation leads to a wide range of clinical features of Noonan syndrome.

    American journal of medical genetics. Part A 2004;128A;1;63-6

  • Somatic PTPN11 mutation with a heterogeneous clonal origin in children with juvenile myelomonocytic leukemia.

    Shimada H, Mori T, Shimasaki N, Shimizu K, Takahashi T and Kosaki K

    Leukemia 2004;18;6;1142-4

  • Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis.

    Loh ML, Vattikuti S, Schubbert S, Reynolds MG, Carlson E, Lieuw KH, Cheng JW, Lee CM, Stokoe D, Bonifas JM, Curtiss NP, Gotlib J, Meshinchi S, Le Beau MM, Emanuel PD and Shannon KM

    Department of Pediatrics, University of California, Rm HSE-302 Box 0519, San Francisco, CA 94143, USA. lohm@itsa.ucsf.edu

    The PTPN11 gene encodes SHP-2 (Src homology 2 domain-containing protein tyrosine Phosphatase), a nonreceptor tyrosine protein tyrosine phosphatase (PTPase) that relays signals from activated growth factor receptors to p21Ras (Ras) and other signaling molecules. Mutations in PTPN11 cause Noonan syndrome (NS), a developmental disorder characterized by cardiac and skeletal defects. NS is also associated with a spectrum of hematologic disorders, including juvenile myelomonocytic leukemia (JMML). To test the hypothesis that PTPN11 mutations might contribute to myeloid leukemogenesis, we screened the entire coding region for mutations in 51 JMML specimens and in selected exons from 60 patients with other myeloid malignancies. Missense mutations in PTPN11 were detected in 16 of 49 JMML specimens from patients without NS, but they were less common in other myeloid malignancies. RAS, NF1, and PTPN11 mutations are largely mutually exclusive in JMML, which suggests that mutant SHP-2 proteins deregulate myeloid growth through Ras. However, although Ba/F3 cells engineered to express leukemia-associated SHP-2 proteins cells showed enhanced growth factor-independent survival, biochemical analysis failed to demonstrate hyperactivation of the Ras effectors extracellular-regulated kinase (ERK) or Akt. We conclude that SHP-2 is an important cellular PTPase that is mutated in myeloid malignancies. Further investigation is required to clarify how these mutant proteins interact with Ras and other effectors to deregulate myeloid growth.

    Funded by: NCI NIH HHS: CA80916, K23 CA80915, P01 CA40046, P30 CA82103; NHLBI NIH HHS: HL04409; NICHD NIH HHS: HD28825

    Blood 2004;103;6;2325-31

  • Genetics and variation in phenotype in Noonan syndrome.

    Jongmans M, Otten B, Noordam K and van der Burgt I

    Department of Human Genetics, University Medical Centre, Nijmegen, The Netherlands.

    Noonan syndrome is a well-known clinical entity comprising multiple congenital anomalies characterized by typical facial features, short stature and congenital heart defect. Approximately 50% of cases are sporadic. Familial cases are generally autosomal dominant. In 2001 a gene responsible for Noonan syndrome, PTPN11, encoding for the non-receptor protein tyrosine phosphatase SHP-2, was identified. Mutation analysis of the PTPN11 gene was carried out in Nijmegen in 150 patients with Noonan syndrome. Mutations were found in 68 patients (45%), the most common being A922G in exon 8. In exon 4 a mutation was found that encoded the C-SH2 domain of the PTPN11 gene in two unique patients who shared some uncommon features. A 218C-->T mutation was found in exon 3 in one patient with Noonan syndrome and mild juvenile myelomonocytic leukaemia.

    Hormone research 2004;62 Suppl 3;56-9

  • 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

  • Mutations of the NF1 gene in children with juvenile myelomonocytic leukemia without clinical evidence of neurofibromatosis, type 1.

    Side LE, Emanuel PD, Taylor B, Franklin J, Thompson P, Castleberry RP and Shannon KM

    Department of Pediatrics, University of California, San Francisco, CA, USA.

    Juvenile myelomonocytic leukemia (JMML) is a pediatric myelodysplastic syndrome that is associated with neurofibromatosis, type 1 (NF1). The NF1 tumor suppressor gene encodes neurofibromin, which regulates the growth of immature myeloid cells by accelerating guanosine triphosphate hydrolysis on Ras proteins. The purpose of this study was to determine if the NF1 gene was involved in the pathogenesis of JMML in children without a clinical diagnosis of NF1. An in vitro transcription and translation system was used to screen JMML marrows from 20 children for NF1 mutations that resulted in a truncated protein. Single-stranded conformational polymorphism analysis was used to detect RAS point mutations in these samples. We confirmed mutations of NF1 in three leukemias, one of which also showed loss of the normal NF1 allele. An NF1 mutation was detected in normal tissue from the only patient tested and this suggests that JMML may be the presenting feature of NF1 in some children. Activating RAS mutations were found in four patients; as expected, none of these samples harbored NF1 mutations. Because 10% to 14% of children with JMML have a clinical diagnosis of NF1, these data are consistent with the existence of NF1 mutations in approximately 30% of JMML cases.

    Funded by: NCI NIH HHS: CA 60407, CA72614

    Blood 1998;92;1;267-72

Literature (9)

Pubmed - human_disease

  • Genome-wide single-nucleotide polymorphism analysis in juvenile myelomonocytic leukemia identifies uniparental disomy surrounding the NF1 locus in cases associated with neurofibromatosis but not in cases with mutant RAS or PTPN11.

    Flotho C, Steinemann D, Mullighan CG, Neale G, Mayer K, Kratz CP, Schlegelberger B, Downing JR and Niemeyer CM

    Division of Pediatric Hematology-Oncology, University of Freiburg, Freiburg, Germany. christian.flotho@uniklinik-freiburg.de

    Juvenile myelomonocytic leukemia (JMML) is a malignant hematopoietic disorder whose proliferative component is a result of RAS pathway deregulation caused by somatic mutation in the RAS or PTPN11 oncogenes or in patients with underlying neurofibromatosis type 1 (NF-1), by loss of NF1 gene function. To search for potential collaborating genetic abnormalities, we used oligonucleotide arrays to analyse over 116 000 single-nucleotide polymorphisms across the genome in 16 JMML samples with normal karyotype. Evaluation of the SNP genotypes identified large regions of homozygosity on chromosome 17q, including the NF1 locus, in four of the five samples from patients with JMML and NF-1. The homozygous region was at least 55 million base pairs in each case. The genomic copy number was normal within the homozygous region, indicating uniparental disomy (UPD). In contrast, the array data provided no evidence for 17q UPD in any of the 11 JMML cases without NF-1. We used array-based comparative genomic hybridization to confirm 17q disomy, and microsatellite analysis was performed to verify homozygosity. Mutational analysis demonstrated that the inactivating NF1 lesion was present on both alleles in each case. In summary, our data indicate that a mitotic recombination event in a JMML-initiating cell led to 17q UPD with homozygous loss of normal NF1, provide confirmatory evidence that the NF1 gene is crucial for the increased incidence of JMML in NF-1 patients, and corroborate the concept that RAS pathway deregulation is central to JMML pathogenesis.

    Oncogene 2007;26;39;5816-21

  • A new PTPN11 mutation in juvenile myelomonocytic leukaemia associated with Noonan syndrome.

    Giovannini L, Cavé H, Ferrero-Vacher C, Boutte P and Sirvent N

    Acta paediatrica (Oslo, Norway : 1992) 2005;94;5;636-7

  • A 3-bp deletion mutation of PTPN11 in an infant with severe Noonan syndrome including hydrops fetalis and juvenile myelomonocytic leukemia.

    Yoshida R, Miyata M, Nagai T, Yamazaki T and Ogata T

    Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development, 3-35-31 Taishido, Setagaya, Tokyo 154-8567, Japan.

    A de novo 3-bp deletion (179-181delGTG) was identified at exon 3 of the PTPN11 gene in a female infant with severe Noonan phenotype including hydrops fetalis and juvenile myelomonocytic leukemia. Since the 3-bp deletion is predicted to result in loss of the 60th glycine in the N-SH2 domain that is directly involved in the intramolecular interaction between the N-SH2 and the PTP domains of the PTPN11 protein, this mutation would disrupt the N-SH2/PTP binding in the absence of a phosphopeptide, leading to an excessive phosphatase activity. The results expand the spectrum of PTPN11 mutations in Noonan syndrome (NS), and suggest that a PTPN11 mutation leads to a wide range of clinical features of Noonan syndrome.

    American journal of medical genetics. Part A 2004;128A;1;63-6

  • Somatic PTPN11 mutation with a heterogeneous clonal origin in children with juvenile myelomonocytic leukemia.

    Shimada H, Mori T, Shimasaki N, Shimizu K, Takahashi T and Kosaki K

    Leukemia 2004;18;6;1142-4

Pubmed - other

  • The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease.

    Kratz CP, Niemeyer CM, Castleberry RP, Cetin M, Bergsträsser E, Emanuel PD, Hasle H, Kardos G, Klein C, Kojima S, Stary J, Trebo M, Zecca M, Gelb BD, Tartaglia M and Loh ML

    University of California, Room HSE-302 Box 0519, San Francisco, CA 94143, USA.

    Germ line PTPN11 mutations cause 50% of cases of Noonan syndrome (NS). Somatic mutations in PTPN11 occur in 35% of patients with de novo, nonsyndromic juvenile myelomonocytic leukemia (JMML). Myeloproliferative disorders (MPDs), either transient or more fulminant forms, can also occur in infants with NS (NS/MPD). We identified PTPN11 mutations in blood or bone marrow specimens from 77 newly reported patients with JMML (n = 69) or NS/MPD (n = 8). Together with previous reports, we compared the spectrum of PTPN11 mutations in 3 groups: (1) patients with JMML (n = 107); (2) patients with NS/MPD (n = 19); and (3) patients with NS (n = 243). Glu76 was the most commonly affected residue in JMML (n = 45), with the Glu76Lys alteration (n = 29) being most frequent. Eight of 19 patients with NS/MPD carried the Thr73Ile substitution. These data suggest that there is a genotype/phenotype correlation in the spectrum of PTPN11 mutations found in patients with JMML, NS/MPD, and NS. This supports the need to characterize the spectrum of hematologic abnormalities in individuals with NS and to better define the impact of the PTPN11 lesion on the disease course in patients with NS/MPD and JMML.

    Funded by: NCI NIH HHS: K24 CA80916, P30 CA82103, R01 CA104282, R01 CA95621; NHLBI NIH HHS: HL074728, HL71207; NICHD NIH HHS: HD01294; Telethon: GGP04172

    Blood 2005;106;6;2183-5

  • Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis.

    Loh ML, Vattikuti S, Schubbert S, Reynolds MG, Carlson E, Lieuw KH, Cheng JW, Lee CM, Stokoe D, Bonifas JM, Curtiss NP, Gotlib J, Meshinchi S, Le Beau MM, Emanuel PD and Shannon KM

    Department of Pediatrics, University of California, Rm HSE-302 Box 0519, San Francisco, CA 94143, USA. lohm@itsa.ucsf.edu

    The PTPN11 gene encodes SHP-2 (Src homology 2 domain-containing protein tyrosine Phosphatase), a nonreceptor tyrosine protein tyrosine phosphatase (PTPase) that relays signals from activated growth factor receptors to p21Ras (Ras) and other signaling molecules. Mutations in PTPN11 cause Noonan syndrome (NS), a developmental disorder characterized by cardiac and skeletal defects. NS is also associated with a spectrum of hematologic disorders, including juvenile myelomonocytic leukemia (JMML). To test the hypothesis that PTPN11 mutations might contribute to myeloid leukemogenesis, we screened the entire coding region for mutations in 51 JMML specimens and in selected exons from 60 patients with other myeloid malignancies. Missense mutations in PTPN11 were detected in 16 of 49 JMML specimens from patients without NS, but they were less common in other myeloid malignancies. RAS, NF1, and PTPN11 mutations are largely mutually exclusive in JMML, which suggests that mutant SHP-2 proteins deregulate myeloid growth through Ras. However, although Ba/F3 cells engineered to express leukemia-associated SHP-2 proteins cells showed enhanced growth factor-independent survival, biochemical analysis failed to demonstrate hyperactivation of the Ras effectors extracellular-regulated kinase (ERK) or Akt. We conclude that SHP-2 is an important cellular PTPase that is mutated in myeloid malignancies. Further investigation is required to clarify how these mutant proteins interact with Ras and other effectors to deregulate myeloid growth.

    Funded by: NCI NIH HHS: CA80916, K23 CA80915, P01 CA40046, P30 CA82103; NHLBI NIH HHS: HL04409; NICHD NIH HHS: HD28825

    Blood 2004;103;6;2325-31

  • Genetics and variation in phenotype in Noonan syndrome.

    Jongmans M, Otten B, Noordam K and van der Burgt I

    Department of Human Genetics, University Medical Centre, Nijmegen, The Netherlands.

    Noonan syndrome is a well-known clinical entity comprising multiple congenital anomalies characterized by typical facial features, short stature and congenital heart defect. Approximately 50% of cases are sporadic. Familial cases are generally autosomal dominant. In 2001 a gene responsible for Noonan syndrome, PTPN11, encoding for the non-receptor protein tyrosine phosphatase SHP-2, was identified. Mutation analysis of the PTPN11 gene was carried out in Nijmegen in 150 patients with Noonan syndrome. Mutations were found in 68 patients (45%), the most common being A922G in exon 8. In exon 4 a mutation was found that encoded the C-SH2 domain of the PTPN11 gene in two unique patients who shared some uncommon features. A 218C-->T mutation was found in exon 3 in one patient with Noonan syndrome and mild juvenile myelomonocytic leukaemia.

    Hormone research 2004;62 Suppl 3;56-9

  • 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

  • Mutations of the NF1 gene in children with juvenile myelomonocytic leukemia without clinical evidence of neurofibromatosis, type 1.

    Side LE, Emanuel PD, Taylor B, Franklin J, Thompson P, Castleberry RP and Shannon KM

    Department of Pediatrics, University of California, San Francisco, CA, USA.

    Juvenile myelomonocytic leukemia (JMML) is a pediatric myelodysplastic syndrome that is associated with neurofibromatosis, type 1 (NF1). The NF1 tumor suppressor gene encodes neurofibromin, which regulates the growth of immature myeloid cells by accelerating guanosine triphosphate hydrolysis on Ras proteins. The purpose of this study was to determine if the NF1 gene was involved in the pathogenesis of JMML in children without a clinical diagnosis of NF1. An in vitro transcription and translation system was used to screen JMML marrows from 20 children for NF1 mutations that resulted in a truncated protein. Single-stranded conformational polymorphism analysis was used to detect RAS point mutations in these samples. We confirmed mutations of NF1 in three leukemias, one of which also showed loss of the normal NF1 allele. An NF1 mutation was detected in normal tissue from the only patient tested and this suggests that JMML may be the presenting feature of NF1 in some children. Activating RAS mutations were found in four patients; as expected, none of these samples harbored NF1 mutations. Because 10% to 14% of children with JMML have a clinical diagnosis of NF1, these data are consistent with the existence of NF1 mutations in approximately 30% of JMML cases.

    Funded by: NCI NIH HHS: CA 60407, CA72614

    Blood 1998;92;1;267-72

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EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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