IntroductionThe deregulation of RAS signal transduction has been implicated in the malignant growth of human cancer cells including myeloid leukemias. 1,2 RAS proto-oncogenes (H-RAS, N-RAS, and K-RAS) encode 21-kd G-proteins that play key roles in signal transduction, proliferation, differentiation, and malignant transformation. 3-5 RAS proteins are produced as cytoplasmatic precursors, which require several posttranslational modifications (eg, prenylation, proteolysis, carboxymethylation, and palmitoylation) for membrane binding and full biologic activity. 3-8 RAS functions as a biologic switch that relays signals from ligand-stimulated tyrosine kinase, cytokine, and heterotrimeric G-protein-coupled receptors to cytoplasmatic mitgen-activated protein kinase (MAPK) cascades. In its activated, GTP-bound state, RAS binds to and activates effector molecules such as Rafs, MEKK, PI-3K, and Ral-GEF. [3][4][5][8][9][10][11][12][13][14] Raf kinases (A-Raf, B-Raf, c-Raf-1) selectively phosphorylate and activate MAPK kinases (MAPKK) MEK-1/2 in the MAPK/ERK pathway. [13][14][15][16][17] MEK-1/2 are dual specificity kinases that activate MAPKs (ERK-1/2). 18,19 The best-characterized ERK substrates are cytoplasmic phospholipase A 2 (cPLA 2 ), ribosomal protein S6 kinases (RSKs), and transcription factors Elk-1 and CREB-1. [18][19][20] The importance of deregulation of ERK signaling in the molecular pathogenesis of myeloid leukemias is underscored by the positioning of several oncogene and tumor suppressor gene products on this pathway. 5,[21][22][23] RAS mutations are frequent genetic aberrations found in 20% to 30% of all human tumors, although the incidences in tumor type vary greatly. 1,2 The most commonly observed RAS mutations arise at sites critical for RAS regulation, namely codons 12, 13, and 61. 1,2,5,9 Additionally, mutations occur at codons 15, 16, 18, and 31. 24,25 These mutations result in abrogation of normal intrinsic or GAP-stimulated GTPase activity of RAS, leading to increased half-lives of mutant RAS-GTP. 5,9,26 Transformation results, at least in part, from deregulated stimulation of mitogenic signal transduction pathways. 1,2,5 The highest incidences of RAS mutations were detected in carcinomas of pancreas (90%), thyroid (50%), colon (50%), and lung (30%). RAS mutations are also frequently observed in myelodysplastic syndromes, acute myeloid leukemias (AML), juvenile myelomonocytic myeloid leukemia (JMML), and multiple myelomas (20%-40%). 1,2,5,[21][22][23] N-RAS is mutated in the majority of cases and presence of the mutation is not associated with any particular FAB type, cytogenetic abnormality, or clinical feature including prognosis. 22 In addition to activation by mutation, RAS is also deregulated in myeloid leukemias by constitutive activation of proto-oncogenes such as receptor or nonreceptor tyrosine kinases (RTKs and NRTKs) or inactivation of tumor suppressor genes. 5,[21][22][23] RTKs are constitutively activated by single point mutations (eg, colonystimulating factor-1 [CSF-1] receptor and c...