TY - JOUR
T1 - Bone Marrow Mesenchymal Stem Cells Support Acute Myeloid Leukemia Bioenergetics and Enhance Antioxidant Defense and Escape from Chemotherapy
AU - Forte, Dorian
AU - García-Fernández, María
AU - Sánchez-Aguilera, Abel
AU - Stavropoulou, Vaia
AU - Fielding, Claire
AU - Martín-Pérez, Daniel
AU - López, Juan Antonio
AU - Costa, Ana S.H.
AU - Tronci, Laura
AU - Nikitopoulou, Efterpi
AU - Barber, Michael
AU - Gallipoli, Paolo
AU - Marando, Ludovica
AU - Fernández de Castillejo, Carlos López
AU - Tzankov, Alexandar
AU - Dietmann, Sabine
AU - Cavo, Michele
AU - Catani, Lucia
AU - Curti, Antonio
AU - Vázquez, Jesús
AU - Frezza, Christian
AU - Huntly, Brian J.
AU - Schwaller, Juerg
AU - Méndez-Ferrer, Simón
N1 - Funding Information:
We thank C. Patrick Reynolds for providing BSO and advice; J. Zhang, I. Frey-Wagner, C. Bernardo-Castiñeira, A. Sommerschield, C. Kapeni, G.C. Fattori, S.B.C. Lama, L. Arranz, K. Attrot, J.B. de Haan, J. Lemarie, A. Moore, and M. Conrad for advice and support; current and former members of the S.M.-F. group for help and discussions; and D. Pask, T. Hamilton, the Central Biomedical Services, Cambridge NIHR BRC Cell Phenotyping Hub, and CNIC Genomics and Bioinformatics Units for technical assistance. D.F. was supported by Associazione Italiana Ricerca sul Cancro (AIRC-Fellowship 20930 for Abroad) and scholarships from Società Italiana di Ematologia (SIE) and Associazione “Amici di Beat Leukemia Dr. Alessandro Cevenini ONLUS” and AIL Bologna ODV. A.S.-A. was supported by a European Hematology Association Research Fellowship and C.L.F.d.C. by a fellowship from Boehringer Foundation. This work was supported by core support grants from the Wellcome Trust ( 203151/Z/16/Z ) and the MRC to the Cambridge Stem Cell Institute , and the Instituto de Salud Carlos III (ISCIII), Ministerio de Ciencia , Innovación y Universidades (MCNU), and Pro CNIC Foundation to CNIC, which is a Severo Ochoa Center of Excellence ( SEV-2015-0505 ). This work was supported by MCNU (Plan Nacional grant SAF-2011-30308 to S.M.-F.; Ramón y Cajal Program grants RYC-2011-09726 to A.S.-A. and RYC-2009-04703 to S.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 Investigación Sanitaria grant PRB3 ( IPT17/0019 - ISCIII-SGEFI / ERDF, ProteoRed), Fundació MaratóTV3 (grant 122/C/2015 ), and “La Caixa” Banking Foundation (project code HR17-00247 ) 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 .
Funding Information:
We thank C. Patrick Reynolds for providing BSO and advice; J. Zhang, I. Frey-Wagner, C. Bernardo-Casti?eira, A. Sommerschield, C. Kapeni, G.C. Fattori, S.B.C. Lama, L. Arranz, K. Attrot, J.B. de Haan, J. Lemarie, A. Moore, and M. Conrad for advice and support; current and former members of the S.M.-F. group for help and discussions; and D. Pask, T. Hamilton, the Central Biomedical Services, Cambridge NIHR BRC Cell Phenotyping Hub, and CNIC Genomics and Bioinformatics Units for technical assistance. D.F. was supported by Associazione Italiana Ricerca sul Cancro (AIRC-Fellowship 20930 for Abroad) and scholarships from Societ? Italiana di Ematologia (SIE) and Associazione ?Amici di Beat Leukemia Dr. Alessandro Cevenini ONLUS? and AIL Bologna ODV. A.S.-A. was supported by a European Hematology Association Research Fellowship and C.L.F.d.C. by a fellowship from Boehringer Foundation. This work was supported by core support grants from the Wellcome Trust (203151/Z/16/Z) and the MRC to the Cambridge Stem Cell Institute, and the Instituto de Salud Carlos III (ISCIII), Ministerio de Ciencia, Innovaci?n y Universidades (MCNU), and Pro CNIC Foundation to CNIC, which is a Severo Ochoa Center of Excellence (SEV-2015-0505). This work was supported by MCNU (Plan Nacional grant SAF-2011-30308 to S.M.-F.; Ram?n y Cajal Program grants RYC-2011-09726 to A.S.-A. and RYC-2009-04703 to S.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 Investigaci?n Sanitaria grant PRB3 (IPT17/0019 - ISCIII-SGEFI/ ERDF, ProteoRed), Fundaci? Marat?TV3 (grant 122/C/2015), and ?La Caixa? Banking Foundation (project code HR17-00247) 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. D.F. M.G.-F. A.S.-A. V.S. C.F. D.M.-P. and C.L.F.d.C. designed and performed experiments and analyzed data. J.A.L. and J.V. performed proteomics studies. M.B. and S.D. performed genomics studies. A.S.H.C. L.T. E.N. and C.F. performed and oversaw metabolomics analysis and contributed to manuscript preparation. P.G. L.M. M.C. L.C. A.C. and B.J.H. provided materials, models, and samples. A.T. performed immunohistochemistry of human samples. J.S. and S.M.-F. planned and supervised the overall study. D.F. M.G.-F. A.S.-A. and S.M.-F. prepared figures and wrote the manuscript. All authors revised and approved the manuscript. The authors declare no competing interests.
Publisher Copyright:
© 2020 The Authors
PY - 2020/11/3
Y1 - 2020/11/3
N2 - 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. Forte et al. reveal that nestin+ bone marrow stromal cells directly contribute to leukemogenesis and chemotherapy resistance in an in vivo model of acute myeloid leukemia. Nestin+ BMSCs support leukemic stem cells through a dual mechanism of increased bioenergetic capacity through OXPHOS and TCA and glutathione-dependent antioxidant defense.
AB - 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. Forte et al. reveal that nestin+ bone marrow stromal cells directly contribute to leukemogenesis and chemotherapy resistance in an in vivo model of acute myeloid leukemia. Nestin+ BMSCs support leukemic stem cells through a dual mechanism of increased bioenergetic capacity through OXPHOS and TCA and glutathione-dependent antioxidant defense.
KW - OXPHOS
KW - TCA cycle
KW - acute myeloid leukemia
KW - antioxidant
KW - bone marrow mesenchymal stem cells
KW - chemotherapy
KW - glutathione
KW - hematopoietic stem cell niche
KW - metabolic adaptation
KW - microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85092219937&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2020.09.001
DO - 10.1016/j.cmet.2020.09.001
M3 - Article
C2 - 32966766
AN - SCOPUS:85092219937
SN - 1550-4131
VL - 32
SP - 829-843.e9
JO - Cell Metabolism
JF - Cell Metabolism
IS - 5
ER -