Myeloid Leukemia Factor 1 inhibits erythropoietin-induced differentiation, cell cycle exit and p27Kip1 accumulation

Myeloid leukemia factor 1 (MLF1) is a novel oncoproteininvolved in translocations associated with acute myeloidleukemia (AML), especially erythroleukemias. In thisstudy, we demonstrate that ectopic expression of Mlf1prevented J2E erythroleukemic cells from undergoingbiological and morphological maturation in response toerythropoietin (Epo). We show that Mlf1 inhibited Epoinducedcell cycle exit and suppressed a rise in the cellcycle inhibitor p27Kip1. Unlike differentiating J2E cells,Mlf1-expressing cells did not downregulate Cul1 andSkp2, components of the ubiquitin E3 ligase complexSCFSkp2 involved in the proteasomal degradation of p27Kip1.In contrast, Mlf1 did not interfere with increases in p27Kip1and terminal differentiation initiated by thyroid hormonewithdrawal from erythroid cells, or cytokine-stimulatedmaturation of myeloid cells. These data demonstrate thatMlf1 interferes with an Epo-responsive pathway involvingp27Kip1 accumulation, which inhibits cell cycle arrestessential for erythroid terminal differentiation.