Abstract
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. The incidence of JMML is increased in children with neurofibromatosis type 1 (NF1).5 NF1, which is diagnosed in TILDE OPERATOR+D9111% 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.
JMML cells from patients with NF1 show biallelic NF1 inactivation and elevated Ras.GTP levels. 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.