Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis

Abstract

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 tyrosine phosphatase SHP‐2 regulates differentiation and apoptosis of individual primary T lymphocytes

“…It is more likely that missing interaction with other signal transduction molecules (e.g. c-Cbl) could explain the absence of ERK inhibition in this case, especially as inhibition is observed with the catalytic inactive SHP-2 C>S. The finding that constitutive activation of SHP-2 does not necessarily lead to increased ERK activation has been described earlier in other cell types [40,41]. In "knockin" mice of constitutive active SHP-2 the authors observed increased ERK phosphorylation only in specific cell types in approximately 50% of the mutant mice [40].…”

Isolation of a distinct class of gain-of-function SHP-2 mutants with oncogenic RAS-like transforming activity from solid tumors

“…Noonan syndrome is also associated with increased risk of juvenile myelomonocytic leukemia (JMML) (Choong et al, 1999), suggesting the role of mutant SHP-2 in leukemogenesis. Indeed, somatic mutations in PTPN11 occur in 35% cases of JMML, 4% of childhood acute myelocytic leukemias and 7% of childhood B-cell acute lymphoblastic leukemias (Tartaglia et al, 2003(Tartaglia et al, , 2004Loh et al, 2004).…”

Juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia

“…55,56 Somatic mutations in PTPN11 represent the most frequent molecular lesion identified to date in JMML, with up to 35% of JMML cases demonstrating PTPN11 mutations, often mutually exclusive with RAS or NF1 mutations. [57][58][59][60][61] Mouse models of these genetic lesions have proven their causal role in myeloproliferative disease development as well as hyperactivation of the Ras pathway and GM-CSF hypersensitivity. [62][63][64][65][66][67] The interested reader can see one of several recent reviews for a more in-depth review of these biochemical and genetic aberrations.…”