TGFβ1 synergizes with FLT3 ligand to induce chemoresistant quiescence in acute lymphoblastic leukemia with MLL gene rearrangements. (October 2017)

• Record Type: Journal Article
• Authors: Tamai, M.; Furuichi, Y.; Kasai, S.; Ando, N.; Harama, D.; Goi, K.; Inukai, T.; Kagami, K.; Abe, M.; Ichikawa, H.; Sugita, K.
• Is Part Of: Leukemia research. Volume 61(2017:Oct.)
• Page Start: 68
• Page End: 76
• Publication Date: 2017-10
• Subjects: Acute lymphoblastic leukemia -- Mixed-lineage leukemia gene -- FLT3 ligand -- TGFβ1 -- Chemoresistance -- Cell cycle arrest; Leukemia -- Periodicals; Leukemia -- Periodicals; Leucémie -- Périodiques; Leukemia; Periodicals; Electronic journals; Electronic journals; 616.9941905
• DOI: 10.1016/j.leukres.2017.08.013
• Languages: English
• ISSNs: 0145-2126

Abstract

Highlights: TGFβ1 mRNA is enhanced by FL stimulation in MLL + ALL cells. TGFβ1 and FL synergistically induce MLL + ALL cells into cell-cycle arrest because of marked prolongation of p27 half-life. Quiescence induced by TGFβ1/FL in MLL + ALL cells showed AraC resistance. AraC resistance in MLL + ALL could be partially restored by inhibitors against receptors for TGFβ1 and/or FL. 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)β1 mRNA levels in MLL + ALL cells, we extensively examined the effect of TGFβ1 on the cell cycle progression and chemosensitivity in MLL + ALL cells, and found that TGFβ1 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 TGFβ1 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 TGFβ1 may become a useful strategy for eradicating MRD in MLL + ALL.