Expression and role of FLT3 in regulation of the earliest stage of normal granulocyte-monocyte progenitor development.

Mice deficient in FLT3 signalling have reductions in early multipotent and lymphoid progenitors, whereas no evident myeloid phenotype has been reported. However, activating mutations of Flt3 are among the most common genetic events in acute myeloid leukemia and mice harbouring internal tandem duplications within Flt3 (Flt3-ITD) develop myeloproliferative disease, with characteristic expansion of granulocyte-monocyte (GM) progenitors, possibly compatible with FLT3-ITD promoting a myeloid fate of multipotent progenitors. Alternatively, FLT3 might be expressed at the earliest stages of GM development. Herein, we investigated the expression, function and role of FLT3 in recently identified early GM progenitors. Flt3-cre fate mapping established that most progenitors and mature progeny of the GM lineage are derived from Flt3 expressing progenitors. A higher expression of FLT3 was found in preGMP compared to GMP, and preGMPs were more responsive to stimulation with FLT3 ligand (FL). Whereas preGMPs and GMPs were reduced in Fl(-/-) mice, megakaryocyte-erythroid progenitors were unaffected and lacked FLT3 expression. Notably, mice deficient in both Thrombopoietin (THPO) and FL, had a more pronounced GM progenitor phenotype than Thpo(-/-) mice, establishing a role of FL in THPO-dependent and independent regulation of GM progenitors, of likely significance for myeloid malignancies with Flt3-ITD mutations.