l-Asparaginase-mediated downregulation of c-Myc promotes 1,25(OH)(2)D-3-induced myeloid differentiation in acute myeloid leukemia cells

Abstract

Treatment of acute myeloid leukemia (AML) largely depends on chemotherapy, but current regimens have been unsatisfactory for long-term remission. Although differentiation induction therapy utilizing 1,25(OH)(2)D-3 (VD3) has shown great promise for the improvement of AML treatment efficacy, severe side effects caused by its supraphysiological dose limit its clinical application. Here we investigated the combinatorial effect of l-asparaginase (ASNase)-mediated amino acid depletion and the latent alternation of VD3 activity on the induction of myeloid differentiation. ASNase treatment enhanced VD3-driven phenotypic and functional differentiation of three-different AML cell lines into monocyte/macrophages, along with c-Myc downregulation. Using gene silencing with shRNA and a chemical blocker, we found that reduced c-Myc is a critical factor for improving VD3 efficacy. c-Myc-dependent inhibition of mTORC1 signaling and induction of autophagy were involved in the enhanced AML cell differentiation. In addition, in a postculture of AML cells after each treatment, ASNase supports the antileukemic effect of VD3 by inhibiting cell growth and inducing apoptosis. Finally, we confirmed that the administration of ASNase significantly improved VD3 efficacy in the prolongation of survival time in mice bearing tumor xenograft. Our results are the first to demonstrate the extended application of ASNase, which is currently used for acute lymphoid leukemia, in VD3-mediated differentiation induction therapy for AML, and suggest that this drug combination may be a promising novel strategy for curing AML. What's new? A new combination could help take down acute myeloid leukemia. VD3, a hormonally active form of vitamin D, can induce terminal differentiation in AML cells, but its nasty side effects prevent it from being a useful treatment. In this article, the authors tested whether amino acid deprivation with l-asparaginase could help VD3 attack AML more efficiently. They found that giving l-asparaginase to tumor-bearing mice along with the VD3 enhanced AML differentiation and improved the mice's survival time, suggesting that it could be very effective in AML treatment.