Inherited predispositions and hyperactive Ras in myeloid leukemogenesis

Abstract

Identifying the molecular basis for inherited cancer predispositions reveals genes that when mutated, play a critical role in the earliest stages of tumorigenesis. Although rare, inherited predispositions to myeloid leukemias have led to a greater understanding of pathways important for myeloid proliferation and maturation. In particular, elucidating why children with neurofibromatosis type 1 (NF1) and Noonan syndrome (NS) are predisposed to juvenile myelomonocytic leukemia (JMML) has uncovered a critical role of hyperactive Ras signaling in normal myeloid growth and leukemogenesis. Here, we review studies of human samples and experiments performed in genetically engineered strains of mice investigating the molecular and biochemical basis of aberrant growth in JMML. These strains model human disease features and provide an opportunity to investigate novel therapeutic strategies that may ultimately cure JMML and other myeloid malignancies characterized by hyperactive Ras.

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

“…SHP-2 mutations are also found in about 35% of patients with nonsyndromic JMML, arguing SHP-2 as the first oncoprotein with tyrosine phosphatase activity (Mohi and Neel, 2007). 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).…”

Juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia

“…45,46 Point mutations of NRAS or KRAS (but not HRAS) are seen in approximately 20-25% of JMML patients and are usually mutually exclusive of patients with NF1 mutations. 40,[47][48][49][50][51] There is a second inherited genetic disorder associated on a clinical basis with JMML, and that disorder is Noonan syndrome. [52][53][54] The causative gene for Noonan syndrome is the PTPN11 gene, which encodes for the protein tyrosine phosphatase SHP2.…”

Mutation analysis of Son of Sevenless in juvenile myelomonocytic leukemia

“…5 NF1, which is diagnosed in B11% of all JMML cases, is an autosomal dominant cancer predisposition syndrome caused by mutations of NF1 coding for neurofibromin, a GTPase activating protein (GAP) for Ras. 5 JMML cells from patients with NF1 show biallelic NF1 inactivation and elevated Ras . GTP levels.…”

“…1 Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative disorder (MPD) characterized by leukocytosis, tissue infiltration by malignant cells, and in vitro hypersensitivity of myeloid progenitors to granulocyte-macrophage colony stimulating factor. 4,5 The incidence of JMML is increased in children with neurofibromatosis type 1 (NF1). 5 NF1, which is diagnosed in B11% of all JMML cases, is an autosomal dominant cancer predisposition syndrome caused by mutations of NF1 coding for neurofibromin, a GTPase activating protein (GAP) for Ras.…”

“…GTP levels. 5 Approximately 25% of JMML cases have somatic RAS mutations, which are identified in patients who do not have NF1. 5 These data and studies in mouse models underscore a crucial role of hyperactive Ras in the pathogenesis of JMML.…”