TGF-β signaling causes ALL quiescence

Interactions of tumor cells with their niches may cause cancer growth, survival and therapy resistance. Signaling by members of the TGF-β superfamily has mainly been studied in the context of solid tumors and quiescent hematopoietic stem cells. In order to investigate the mechanisms mediating dormancy of residual acute lymphoblastic leukemia (ALL) in the bone marrow niche, we first examined the effect of TGF-β on ALL cell proliferation in vitro. Treatment of cell lines carrying TEL-AML1 and E2A-PBX1 fusions with TGF-β lead to an exit of the cell cycle as evidenced by propidium iodine, BrdU and Ki-67-stainings. In contrast, ALL cells with the high-risk BCR-ABL1 fusion entered apoptosis. TGF-β effects could be counteracted by the selective TGF-β receptor I inhibitor LY364947. Varying degrees of pathway activation were shown by differential Smad2 phosphorylation and expression levels of TGF-β pathway components in these cells. Our data suggests that TGF-β can mediate cell cycle exit by activating the TGF-βR1/Smad-pathway in ALL cell lines with TEL-AML1 and E2A-PBX1 fusions associated with late relapses in patients. TGF-βsignaling may thus be connected with ALL residual disease in certain genetic subgroups.