ABSTRACT
Fms-like tyrosine kinase 3 (FLT3) is highly expressed in mixed-lineage leukemia (MLL) gene-rearranged acute lymphoblastic leukemia (MLL+ALL) with a dismal prognosis. We previously reported that FLT3 ligand (FL) stimulation induced cell cycle arrest in MLL+ALL cells leading to resistance against anti-leukemic agents. Given that FL stimulation enhanced transforming growth factor (TGF)ß1 mRNA levels in MLL+ALL cells, we extensively examined the effect of TGFß1 on the cell cycle progression and chemosensitivity in MLL+ALL cells, and found that TGFß1 stimulation induced MLL+ALL cells into cell cycle arrest resistant to arabinosyl cytosine; its effect was markedly enhanced in synergy with FL. Thus, it is likely that TGFß1 and FL, both abundantly produced by bone marrow stromal cells, function in a coordinated manner to render MLL+ALL cells chemoresistant, which should lead to the development of minimal residual disease (MRD) resulting in relapse. The use of inhibitors against FLT3 and TGFß1 may become a useful strategy for eradicating MRD in MLL+ALL.
