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 p21 Ras (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. (Blood.

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-AmericanBritish (FAB) morphology M5 AML (P ¼ 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. Leukemia (2004) [2][3][4] Uncovering other mutations that perturb the RTK/Ras signaling pathways could further illuminate the biology of AML, provide new independent prognostic markers, and/or identify new therapeutic targets.The PTPN11 gene encodes SHP-2, a nonreceptor protein tyrosine phosphatase that relays signals from activated growth factor receptors to Ras and other signaling molecules. 5 Germline mutations in PTPN11 are a major cause of Noonan syndrome (NS). 6,7 Children with NS are at increased risk of developing juvenile myelomonocytic leukemia (JMML), a relentless myeloproliferative disorder characterized by overproduction of myelomonocytic cells that infiltrate spleen, liver, and skin, among other organs. [8][9][10] Most children with JMML are boys. [8][9][10] We and others have recently reported that up to 35% of patients with JMML harbor missense PTPN11 mutations, which are largely exclusive of RAS and NF1 alterations. 11,12 All of these mutations are predicted to activate SHP-2 phosphatase activity by disrupting the inhibitory interaction between the N-SH2 and PTP domains of the protein. Although the biochemical data are inconclusive, genetic studies suggest that the hyperactive PTPN11 mutations found in JMML contribute to leukemia growth by deregulating the Ras pathway. 11,12 Based on the existence of NRAS and KRAS mutations in AML and JMML, we reasoned that mutations in PTPN11 might also occur in both diseases. To address this question, we screened a well-characterized cohort of AML specimens from children enrolled on Children's Cancer Group (CCG) clinical trials 2941 and 2961 for mutations in PTPN11 and correlated these data with clinical and molecular data. Materials and methods Patients and therapyBone marrow specimens from 298 patients with de novo AML registered on protocols CCG 2941 and 2961 were included in this study. A total of 278 specimens had adequate DNA for analysis. The diagnosis of AML...

In a retrospective analysis, we previously reported that children whose leukemia cells harbored the TEL/AML1 gene rearrangement have excellent outcomes. From 1996 to 2000, we conducted a prospective study to determine the incidence and outcomes of children with TEL/AML1-positive acute lymphoblastic leukemia (ALL). Children with newly diagnosed ALL were treated on DFCI ALL Consortium Protocol 95-01. Patients were risk stratified primarily by current National Cancer Institute (NCI)-Rome risk criteria. With a median follow-up of 5.2 years, the 5-year event-free survival for TEL/AML1-positive patients was 89% compared with 80% for TEL/AML1-negative B-precursor patients (P ‫؍‬ .05). The 5-year overall survival rate was 97% among TEL/AML-positive patients compared with 89% among TEL/ AML1-negative patients (P ‫؍‬ .03). However, in a multivariable analysis, risk group (age and leukocyte count at diagnosis) and asparaginase treatment group, but not TEL/AML1 status, were found to be independent predictors of outcome. We conclude that TEL/AML1-positive patients have excellent outcomes, confirming our previous findings. However, factors such as age at diagnosis and presenting leukocyte count should be taken into consideration when treating this group of patients. (Blood. 2006;107:4508-4513)

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