Two consistent abnormalities have been demonstrated by in vitro studies of juvenile chronic myelomonocytic leukemia (JCML) recently proposed to be renamed juvenile myelomonocytic leukemia (JMML) patients: the exuberant“spontaneous” growth of colony forming units-granulocyte/macrophage (CFU-GM) in the absence of exogenous growth factors, and the impaired growth of normal hemopoietic progenitors. Spontaneous cell growth has been ascribed to the peculiar hypersensitivity of the JMML bone marrow or peripheral blood progenitors to very low levels of cytokines and growth factors probably produced by adherent cells. The observed hypersensitivity response appears to be quite selective, as it occurs in tests with GM-CSF, but not other growth factors regulating early steps of myelopoiesis, such as interleukin-3 (lL-3) or granulocytecolony stimulating factor (G-CSF). To date, binding studies and molecular analysis of the GM-CSF receptor have revealed no abnormalities, although several provocative clues have emerged. During neoplastic transformation of myeloid progenitors, RAS genes often acquire activating point mutations that lead to elevated levels of Ras-GTP, resulting in disregulation of this common signal transduction pathway, which is also triggered by GM-CSF in growth factor-dependent cell lines. In this regard, mutated RAS genes have been found in 30% of cases of JMML. In a series of 11 JMML patients, nucleotide sequence analysis showed single nucleotide substitutions involving codons 12 (GGT→TGT) and 13(GGT→GAT) in exon 1 and codons 61 in exon 2 (CAA→CTA). Loss of the normal NF1 allele is a common finding in JMML cells from patients with NF1. As a tumor suppressor, the NF1 protein acts as GTPase, which in turn downregulates Ras-GTP. Primary leukemic cells from children with NF1 show a selective decrease in NF1-like GTPase activating protein (GAP) activity for RAS, but retain normal cellular GAP activity. Leukemic cells also show an elevated percentage of RAS in the GTP-bound conformation. Activation of the JAK-2 tyrosine kinase or over expression of the Shc proteins might contribute to GM-CSF hypersensitivity in cases of JMML that lack either RAS or NFI mutations.