Acquired PTPN11 mutations occur rarely in adult patients with myelodysplastic syndromes and chronic myelomonocytic leukemia

Loh, Mignon L.; Martinelli, Simone; Cordeddu, Viviana; Reynolds, Melissa G.; Vattikuti, Shashaank; Lee, Connie M.; Wulfert, Michael; Germing, Ulrich; Haas, Peter; Niemeyer, Charlotte M.; Beran, Miloslav; Strom, Sara S.; Lübbert, Michael; Sorcini, Mariella; Estey, Elihu H.; Gattermann, Norbert; Tartaglia, Marco

doi:10.1016/j.leukres.2004.10.001

Cited by 61 publications

(35 citation statements)

References 11 publications

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“…Two mutations, 155C Ͼ T (Thr52Ser) and 226-227GA Ͼ AT (Glu76Met), had not been previously documented in JMML or other malignancies. [3][4][5][6]19,20 Figure 1 shows an updated compendium of PTPN11 mutations previously documented in JMML or NS/MPD combined with the current cohort of 77 newly reported patients. The series includes 107 JMML cases, 19 patients with NS/MPD, and 243 patients with NS or LS.…”

Section: Resultsmentioning

confidence: 99%

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

Kratz

Niemeyer

Castleberry

et al. 2005

Blood

228

196

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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 IntroductionThe PTPN11 proto-oncogene encodes Src-homology tyrosine phosphatase 2 (SHP-2), a protein tyrosine phosphatase with a role in signal transduction and hematopoiesis. 1,2 Somatic PTPN11 mutations exist in 35% of juvenile myelomonocytic leukemia (JMML) specimens and are less frequent in other leukemias. 3-6 SHP-2 relays signals from activated growth factor receptors to Ras. PTPN11, KRAS2, NRAS, and NF1 mutations are found in mutually exclusive subsets of patients with JMML. 3,4 These data support the hypothesis that hyperactive Ras signaling plays a central role in JMML.Germ-line PTPN11 mutations cause approximately 50% of cases of Noonan syndrome (NS), 7,8 a congenital disorder characterized by facial anomalies, short stature, and heart defects. 9 Whereas NS is frequently inherited as an autosomal dominant condition, almost half of the constitutional PTPN11 mutations found in NS arise sporadically. Germ-line PTPN11 mutations are also found in patients with multiple lentigene syndrome (LS), a rare developmental disorder clinically related to NS. 9 Infants with NS are predisposed to developing a myeloproliferative disorder (NS/MPD), which may regress without treatment or follow an aggressive clinical course similar to JMML. 10-14 By contrast, cases of JMML that arise in patients without NS have a poor prognosis without hematopoietic stem cell transplantation. [15][16][17][18] Recent studies show that children with JMML have improved outcomes when they are treated aggressively early in the course of disease. 18 Therefore, differentiating JMML from NS/MPD and identifying patients with NS/MPD who will require aggressive treatment are important clinical questions. We identify PTPN11 mutations in 77 newly reported patients with JMML and NS/MPD, and compare the mutational spectrum in JMML, NS/MPD, and NS/LS to determine if genotype-phenotype correlations exist that may help guide diagnosis and clinical management. Study designTissue samples (bone marrow, peripheral blood, and, rarely, buccal swab and skin fibroblasts) from patients with JMML and NS/MPD were collected under Institutional...

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Section: Resultsmentioning

confidence: 99%

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

Kratz

Niemeyer

Castleberry

et al. 2005

Blood

228

196

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“…In MDS, mutations of the N-RAS gene have been known to be a frequent (B10%) genetic alteration, 35 and these typically occur during transformation to AML. However, mutations of PTPN11 have been reported to be rare in adult MDS (2 of 189 MDS/AML, 1.1%), [36][37][38] although they have been frequently found in childhood MDS. 25 Mutations of the NF1 gene are also very rare in adult MDS.…”

Section: Discussionmentioning

confidence: 99%

Hyperactivation of the RAS signaling pathway in myelodysplastic syndrome with AML1/RUNX1 point mutations

Niimi

Harada

et al. 2006

Leukemia

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AML1/RUNX1 mutations have been reported frequently in myelodysplastic syndrome (MDS) patients, especially those diagnosed with refractory anemia with excess blast (RAEB), RAEB in transformation (RAEBt), or AML following MDS (these categories are defined as MDS/AML). Although AML1 mutations are suspected to play a pivotal role in the development of MDS/ AML, acquisition of additional genetic alterations is also necessary. We analyzed gene alterations in MDS/AML patients with AML1 mutations, comparing them to alterations in those without an AML1 mutation. AML1 mutations were significantly associated with À7/7q-, whereas MDS/AML patients without AML1 mutations showed a high frequency of À5/5q-and a complex karyotype. Patients with AML1 mutations showed more mutations of their FLT3, N-RAS, PTPN11, and NF1 genes, resulting in a significantly higher mutation frequency for receptor tyrosine kinase (RTK)-RAS signaling pathways in AML1-mutated MDS/AML patients compared to AML1-wild-type MDS/AML patients (38% versus 6.3%, Po0.0001). Conversely, p53 mutations were detected only in patients without AML1 mutations. Furthermore, blast cells of the AML1-mutated patients expressing surface c-KIT, and SHP-2 mutants contributed to prolonged and enhanced extracellular signalregulated kinase activation following stem cell factor stimulation. Our results suggest that MDS/AML arising from AML1/ RUNX1 mutations has a significant association with À7/7q-alteration, and frequently involves RTK-RAS signaling pathway activation.

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“…Indeed, somatic missense PTPN11 mutations have been demonstrated to occur in approximately one-third of isolated JMML as well as in variable proportions of other myeloid and lymphoid malignancies of childhood [Tartaglia et al, 2003[Tartaglia et al, , 2004aLoh et al, 2004a, b;Kratz et al, 2005]. The prevalence of PTPN11 mutations among adult patients with myeloid or lymphoid disorders appears to be considerably lower than observed among pediatric cases [Hugues et al, 2005;Loh et al, 2005;Tartaglia et al, 2006], even though SHP2 overexpression has been documented in adult human leukemia [Xu et al, 2005]. Similarly, PTPN11 is only rarely mutated in nonhematologic cancers [Bentires-Alj et al, 2004;Chen et al, 2006;Martinelli et al, 2006Martinelli et al, , 2009.…”

Section: Ptpn11mentioning

confidence: 99%

Noonan Syndrome: Clinical Aspects and Molecular Pathogenesis

2010

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Noonan syndrome (NS) is a relatively common, clinically variable and genetically heterogeneous developmental disorder characterized by postnatally reduced growth, distinctive facial dysmorphism, cardiac defects and variable cognitive deficits. Other associated features include ectodermal and skeletal defects, cryptorchidism, lymphatic dysplasias, bleeding tendency, and, rarely, predisposition to hematologic malignancies during childhood. NS is caused by mutations in the PTPN11, SOS1, KRAS, RAF1, BRAF and MEK1 (MAP2K1) genes, accounting for approximately 70% of affected individuals. SHP2 (encoded by PTPN11), SOS1, BRAF, RAF1 and MEK1 positively contribute to RAS-MAPK signaling, and possess complex autoinhibitory mechanisms that are impaired by mutations. Similarly, reduced GTPase activity or increased guanine nucleotide release underlie the aberrant signal flow through the MAPK cascade promoted by most KRAS mutations. More recently, a single missense mutation in SHOC2, which encodes a cytoplasmic scaffold positively controlling RAF1 activation, has been discovered to cause a closely related phenotype previously termed Noonan-like syndrome with loose anagen hair. This mutation promotes aberrantly acquired N-myristoylation of the protein, resulting in its constitutive targeting to the plasma membrane and dysregulated function. PTPN11, BRAF and RAF1 mutations also account for approximately 95% of LEOPARD syndrome, a condition which resembles NS phenotypically but is characterized by multiple lentigines dispersed throughout the body, café-au-lait spots, and a higher prevalence of electrocardiographic conduction abnormalities, obstructive cardiomyopathy and sensorineural hearing deficits. These recent discoveries demonstrate that the substantial phenotypic variation characterizing NS and related conditions can be ascribed, in part, to the gene mutated and even the specific molecular lesion involved.

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Acquired PTPN11 mutations occur rarely in adult patients with myelodysplastic syndromes and chronic myelomonocytic leukemia

Cited by 61 publications

References 11 publications

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

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

Hyperactivation of the RAS signaling pathway in myelodysplastic syndrome with AML1/RUNX1 point mutations

Noonan Syndrome: Clinical Aspects and Molecular Pathogenesis

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