Model of cooperativity of activating mutations in FLT3 and gene rearrangements involving hematopoietic transcription factors.

The model of cooperativity is based in part on the observation that FLT3-ITD mutations have been associated with all FAB subtypes of AML, and with the majority of known chromosomal translocations associated with AML, including the t(8;21), inv(16), t(15;17), and MLL gene rearrangements. We hypothesize that there are 2 broad classes of mutations that contribute to AML: class I and class II mutations. FLT3-ITD would be exemplary of a class I mutations that, alone, confers a proliferative and survival advantage to hematopoietic progenitors but does not affect differentiation. Consistent with this hypothesis, expression of FLT3-ITD alone in a murine BMT assay results in a myeloproliferative phenotype characterized by leukocytosis and normal differentiation. Another example of class I mutations would be activating mutations in N-RAS or K-RAS in AML. In contrast, class II mutations would be exemplified by AML1/ETO, CBFβ/SMMHC, PML/RARα, and MLL-related fusion genes appear to impair hematopoietic differentiation, but are not sufficient to cause leukemia when expressed alone. We hypothesize that expression of both classes of mutations results in the AML phenotype characterized by enhanced proliferation and survival capacity of progenitor cells, and by impaired differentiation. The hypothesis has important implications in approach to novel therapies of AML, in that molecular targeting of both FLT3-ITD and fusion proteins involving transcription factors may improve outcome in AML.