title: Targeting autophagy to overcome chemoresistance in acute myleogenous leukemia.
abstract: Therapeutic inhibition of macroautophagy/autophagy is expected to increase chemosensitivity of cancers and alter tumor-stroma interdependence. The hypoxic, metabolically challenged bone marrow microenvironment confers chemoresistance to leukemia cells. The impact of autophagy inhibition in the context of microenvironment-mediated resistance in leukemia is less explored. Our recent studies demonstrated that co-culture of acute myelogenous leukemia (AML) cells with marrow-derived mesenchymal stromal cells (MSC) induces autophagy in AML cells and increases resistance to genotoxic agents (cytarabine and idarubicin). Genetic silencing of ATG7 in AML enhances the sensitivity to these genotoxic agents, an effect that was more pronounced with concomitant silencing of ATG7 in AML and MSCs. Mechanistically, the increased sensitivity of AML cells to genotoxic agents is associated with alteration of BCL2 family proteins, particularly transcriptional upregulation of PMAIP1/NOXA. In a disseminated AML model in immunocompromised mice, ATG7 knockdown in AML cells results in better survival compared to control mice when treated with chemotherapy. Our studies support the therapeutic role of autophagy inhibition, specifically ATG7 inhibition, in AML.
authors: a Department of Leukemia , Section of Molecular Hematology and Therapy, MD Anderson Cancer Center , Houston , TX USA.
authors: Sujan
authors: S
authors: Piya
authors: a Department of Leukemia , Section of Molecular Hematology and Therapy, MD Anderson Cancer Center , Houston , TX USA.
authors: Michael
authors: M
authors: Andreeff
authors: a Department of Leukemia , Section of Molecular Hematology and Therapy, MD Anderson Cancer Center , Houston , TX USA.
authors: Gautam
authors: G
authors: Borthakur
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003561:Cytarabine / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D020868:Gene Silencing; D006801:Humans; D015255:Idarubicin / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects; D051379:Mice; D016513:Mice, SCID; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D003561:Cytarabine; D015255:Idarubicin
keywords: ATG7; NOXA; chemoresistance; microenvironment; stroma-mediated autophagy