Bone Marrow Mesenchymal Stem Cells Support Acute Myeloid Leukemia Bioenergetics and Enhance Antioxidant Defense and Escape from Chemotherapy
Like normal hematopoietic stem cells, leukemic stem cells depend on their bone marrow (BM) microenvironment for survival, but the underlying mechanisms remain largely unknown. We have studied the contribution of nestin+ BM mesenchymal stem cells (BMSCs) to MLL-AF9-driven acute myeloid leukemia (AML) development and chemoresistance in vivo. Unlike bulk stroma, nestin+ BMSC numbers are not reduced in AML, but their function changes to support AML cells, at the expense of non-mutated hematopoietic stem cells (HSCs). Nestin+ cell depletion delays leukemogenesis in primary AML mice and selectively decreases AML, but not normal, cells in chimeric mice. Nestin+ BMSCs support survival and chemotherapy relapse of AML through increased oxidative phosphorylation, tricarboxylic acid (TCA) cycle activity, and glutathione (GSH)-mediated antioxidant defense. Therefore, AML cells co-opt energy sources and antioxidant defense mechanisms from BMSCs to survive chemotherapy. ; This work was supported by core support grants from the Well-come Trust (203151/Z/16/Z) and the MRC to the Cambridge Stem Cell Insti-tute, and the Instituto de Salud Carlos III (ISCIII), Ministerio de Ciencia, Innovacion y Universidades (MCNU), and Pro CNIC Foundation to CNIC, which is a Severo Ochoa Center of Excellence (SEV-2015-0505). This work was sup-ported by MCNU (Plan Nacional grant SAF-2011-30308 to S.M.-F.; Ramon y Cajal Program grants RYC-2011-09726 to A.S.-A. and RYC-2009-04703 toS.M.-F.); Marie Curie Career Integration Program grants (FP7-PEOPLE-2011-RG-294262/294096) to A.S.-A. and S.M.-F.; Spanish Ministry of Science, Innovation and Universities (BIO2015-67580-P and PGC2018-097019-B-I00), Carlos III Institute of Health-Fondo de Investigacio ́n Sanitaria grantPRB3 (IPT17/0019 - ISCIII-SGEFI/ ERDF, ProteoRed), Fundacio Marato TV3(grant 122/C/2015), and ''La Caixa'' Banking Foundation (project codeHR17-00247) to J.V.; the Medical Research Council grant MRC_MC_UU_12022/6 to C.F.; an ERC award (COMAL: 647685) and a CRUK Programme Award to B.J.H.; the Swiss National Science Foundation (SNF, 31003A_173224/1 & 31003A_149714) and the Gertrude von Meissner Foundation (Basel, Switzerland) to J.S.; ISCIII Spanish Cell Therapy Network TerCel, ConSEPOC-Comunidad de Madrid grant (S2010/BMD-2542), National Health Service Blood and Transplant (United Kingdom), European Union's Horizon 2020 research (ERC-2014-CoG-648765), and a Program Foundation Award (C61367/A26670) from Cancer Research UK to S.M.-F., who was also supported in part by an International Early Career Scientist grant of the Howard Hughes Medical Institute. ; Sí