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Acknowledgements This work was funded by a Biotechnology and Biological Sciences Research Council (BBSRC) Collaborative Awards in Science and Engineering (CASE) award (to Huan Cao) as well as Wellcome Trust (089821/Z/09/Z) and UK Medical Research Council (MRC) (G0901682) grants. Alexander D. Barrow was funded by a Marie Curie International Outgoing Fellowship (EC 236932). John Trowsdale received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement No. 695551). ; Peer reviewed ; Publisher PDF

© The Author(s). ; [Background]: Acute myeloid leukemia (AML) is the most common acute leukemia in adults and has an unacceptably low cure rate. In recent years, a number of new treatment strategies and compounds were developed for the treatment of AML. There were several randomized controlled clinical trials with the objective to improve patients' management and patients' outcome in AML. Unfortunately, these trials are not always directly comparable since they do not measure the same outcomes, and currently there are no core outcome sets that can be used to guide outcome selection and harmonization in this disease area. The HARMONY (Healthcare Alliance for Resourceful Medicine Offensive against Neoplasms in Hematology) Alliance is a public-private European network established in 2017 and currently includes 53 partners and 32 associated members from 22 countries. Amongst many other goals of the HARMONY Alliance, Work Package 2 focuses on defining outcomes that are relevant to each hematological malignancy. Accordingly, this pilot study will be performed to define a core outcome set in AML. ; [Methods]: The pilot study will use a three-round Delphi survey and a final consensus meeting to define a core outcome set. Participants will be recruited from different stakeholder groups, including patients, clinicians, regulators and members of the European Federation of Pharmaceutical Industries and Associations. At the pre-Delphi stage, a literature research was conducted followed by several semi-structured interviews of clinical public and private key opinion leaders. Subsequently, the preliminary outcome list was discussed in several multi-stakeholder face-to-face meetings. The Delphi survey will reduce the preliminary outcome list to essential core outcomes. After completion of the last Delphi round, a final face-to-face meeting is planned to achieve consensus about the core outcome set in AML. ; [Discussion]: As part of the HARMONY Alliance, the pilot Delphi aims to define a core outcome set in AML on the basis of a multi-stakeholder consensus. Such a core outcome set will help to allow consistent comparison of future clinical trials and real-world evidence research and ensures that appropriate outcomes valued by a range of stakeholders are measured within future trials. ; This work was funded through the Innovative Medicines Initiative 2 joint undertaking and listed under grant agreement 116026. This joint undertaking receives support from the European Union's Horizon 2020 research and innovation program and the EFPIA. An additional cash grant was obtained from Bayer AG for conducting the Delphi survey development

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

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. ; D.F. was supported by Associazione Italiana Ricerca sul Cancro (AIRCFellowship 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-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_173224/1) 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 Programme 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.