title: l-Asparaginase-mediated downregulation of c-Myc promotes 1,25(OH)2D3-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)2D3(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.
authors.affiliation: Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea.
authors.forename: Ju Han
authors.initials: JH
authors.lastname: Song
authors.affiliation: Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea.
authors.forename: Eunchong
authors.initials: E
authors.lastname: Park
authors.affiliation: Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea.
authors.forename: Myun Soo
authors.initials: MS
authors.lastname: Kim
authors.affiliation: Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea.
authors.forename: Kyung-Min
authors.initials: KM
authors.lastname: Cho
authors.affiliation: Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea.
authors.forename: Su-Ho
authors.initials: SH
authors.lastname: Park
authors.affiliation: Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea.
authors.forename: Arim
authors.initials: A
authors.lastname: Lee
authors.affiliation: Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea.
authors.forename: Jiseon
authors.initials: J
authors.lastname: Song
authors.affiliation: Department of Hematology, Chonnam National University Hwasun Hospital, Hwasun, 58128, Republic of Korea.
authors.forename: Hyeoung-Joon
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Pharmacology and Dental Therapeutics, Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju, 61186, Republic of Korea.
authors.forename: Jeong-Tae
authors.initials: JT
authors.lastname: Koh
authors.affiliation: Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea.
authors.forename: Tae Sung
authors.identifier: 0000-0002-0384-4407
authors.initials: TS
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001215:Asparaginase / Q000378:metabolism*; D015153:Blotting, Western; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D002117:Calcitriol / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D050071:Bone Density Conservation Agents; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D001215:Asparaginase; D002117:Calcitriol
keywords: 1,25(OH)2D3; acute myeloid leukemia; autophagy; c-Myc; l-asparaginase; mTORC1; myeloid differentiation