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The recent finding of a somatic point mutation in the JAK2 tyrosine kinase (V617F) pseudokinase domain of the majority of patients with myloproliferative disorders has greatly increased the understanding of the molecular pathways deregulated in these diseases and has provided a potential therapeutic target. FLT3, a receptor tyrosine kinase, has been shown to contain internal duplications in 25 - 30% of patients with acute myeloid leukemia and is correlated with poor prognosis. The association of these mutations with abnormal proliferation of myeloid cells prompted us to study patients with CMML, a myelodysplastic disorder that can also present with myeloproliferative characteristics of leukocytosis and splenomegaly. Mutations of JAK2 or FLT3 would provide both a biologic insight and treatment strategies for this subgroup of CMML which until now has been identified by WBC counts greater that 13,000/uL. We isolated DNA from bone marrow mononuclear cells of 67 patients with CMML, 28 with WBCs greater than 13,000/uL, and 39 with lower WBCs. Using PCR followed by sequencing, only one patient was found to have a JAK2 mutation. Similarly only one patient was found to be carrying a FLT3 internal duplication. Both of these patients however, had proliferative clinical features. These data confirm the previous low incidence of JAK2 mutations in 3/119 patients with CMML1. Thus, it appears that mutations in the JAK2 and FLT3 tyrosine kinase genes are only infrequently involved in the pathobiology of CMML. It remains possible that other genes in these two pathways are deregulated in CMML, or that other tyrosine kinase genes are mutated leading to similar clinical features. 1. Steensma DP, et al. The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both “atypical” myeloproliferative disorders and myelodysplastic syndromes. Blood 106;4:1207-1209, 2005.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]