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

Abstract

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.

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

“…Furthermore, the observation that approximately 25% of JMML cases possess oncogenic RAS mutation indicates that deregulation of the RAS-effector pathways through gain-of-function mutation of RAS or SHP-2 plays a causative role in the development of JMML (Lauchle et al, 2006). Intriguingly, the individual amino-acid substitutions of SHP-2 identified in Noonan syndrome and sporadic JMML hardly overlap each other , and leukemia (JMML)-specific SHP-2 mutants generally exhibit highly elevated basal phosphatase activity compared with the basal phosphatase level of wild type or Noonan-specific SHP-2 (Tartaglia et al, 2003Keilhack et al, 2005).…”

“…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).…”

“…Binding of a phosphotyrosinecontaining peptide to the N-SH2 domain alleviates the autoinhibition to form an open conformation with active phosphatase activity (Hof et al, 1998;Neel et al, 2003). Most if not all mutations found in Noonan syndrome or leukemia affect residues in the N-SH2 domain or PTP domain that abolish the autoinhibitory interaction and thereby exhibit increased basal phosphatase activity (Tartaglia et al, 2003). Hence, SHP-2 is a bona fide oncoprotein, gain-of-function mutation of which is involved in leukemogenesis.…”

Linking epithelial polarity and carcinogenesis by multitasking Helicobacter pylori virulence factor CagA

“…Notably, Noonan patients exhibit increased risk of malignancies, especially juvenile myelomonocytic leukemia and neuroblastoma. Furthermore, PTPN11 mutations have been found in sporadic cases of juvenile myelomonocytic leukemia, childhood myelodysplastic syndrome, acute B-lymphocytic leukemia and acute myelocytic leukemia as well as some solid tumors such as neuroblastoma (Tartaglia et al, 2003;Bentires-Alj et al, 2004). Hence, SHP-2 is a bona fide human oncoprotein like Ras (Mohi and Neel, 2007).…”

Co‐occurrence of hypertrophic cardiomyopathy and juvenile myelomonocytic leukemia in a neonate with Noonan syndrome, leading to premature death

“…p.Thr73Ile is associated with JMML/MPD in individuals with NS 20, 21. The prognosis of patients with NS associated with JMML is much worse than those with MPD who do not fully meet the diagnostic criteria for JMML (a two‐year overall survival rate, 40% vs 100%) 17.…”