Abstract
FLT3 internal tandem duplication (ITD) activating mutations are among the most common genetic events in acute myelogenous leukemia (AML) and confer a poor clinical prognosis. Despite their known transforming properties, the effects of constitutive FLT3 signaling on multipotent stem and progenitor cells and hematopoietic differentiation are not well understood. Here we report a novel murine model harboring an ITD mutation in the endogenous murine Flt3 locus. These mice exhibit a myeloproliferative disease (MPD) resembling human chronic myelomonocytic leukemia (CMML) and concomitant with the murine phenotype, we identified FLT3-ITD mutations in a proportion of human CMML. Disease was more pronounced in animals that were bi-allelic for the ITD mutation (Flt3ITD/ITD) and these findings correlated with an increase in number, cell cycling and survival of multipotent stem and progenitor cells in Flt3+/ITD and Flt3ITD/ITD mice in a dose-dependent manner. Moreover, Flt3 mutant animals demonstrated expansion of granulocyte-monocyte (GMP) progenitors as well as reduction in erythroid progenitors and a block in normal B cell development. Together, these findings provide novel insights into the consequences of dysregulated FLT3 tyrosine kinase signaling on primitive hematopoietic progenitor quiescence, function and cell fate and how these effects contribute to the pathogenesis of acute myelogenous leukemia.
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