Abstract

Acute myeloid leukaemia (AML) is distinguished by the generation of dysfunctional leukaemic blasts, and patients characteristically suffer from fatal infections and anaemia due to insufficient normal myelo-erythropoiesis. Direct physical crowding of bone marrow (BM) by accumulating leukaemic cells does not fully account for this haematopoietic failure. Here, analyses from AML patients were applied to both in vitro co-culture platforms and in vivo xenograft modelling, revealing that human AML disease specifically disrupts the adipocytic niche in BM. Leukaemic suppression of BM adipocytes led to imbalanced regulation of endogenous haematopoietic stem and progenitor cells, resulting in impaired myelo-erythroid maturation. In vivo administration of PPARγ agonists induced BM adipogenesis, which rescued healthy haematopoietic maturation while repressing leukaemic growth. Our study identifies a previously unappreciated axis between BM adipogenesis and normal myelo-erythroid maturation that is therapeutically accessible to improve symptoms of BM failure in AML via non-cell autonomous targeting of the niche.

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Acknowledgements

This work was supported by a research grant to M.B. from the Marta and Owen Boris Foundation and Canadian Cancer Society Research Institute. A.L.B. was supported by graduate research scholarships: Ontario Graduate Scholarship, National Science and Engineering Research Council (NSERC) and the Jans Graduate Scholarship in Stem Cell Research. J.C.R. was supported by a doctoral scholarship from the Canadian Institute of Health Research (CIHR) and K.R.S. was supported by the NSERC Create M3 program. Y.D.B. was funded by the Quebec Health Research Funds (FRQS) and CIHR, and holds a fellowship from the Cancer Research Society (CRS). M.B. is a Canada Research Chair in Stem Cell Biology and Regenerative Medicine. We acknowledge M. Graham for human sample processing, as well as A. Fiebig-Comyn, W. Whittaker, L. Robson and A. Scott for assistance with animal husbandry and in vivo experiments. We thank L. May, M. J. Smith and M. Bruni for assistance with histology and immunofluorescence staining. We also thank C. Magruder and C. Hopkins for illustrative images.

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Affiliations

  1. Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario L8N 3Z5, Canada

    • Allison L. Boyd
    • , Jennifer C. Reid
    • , Kyle R. Salci
    • , Lili Aslostovar
    • , Yannick D. Benoit
    • , Zoya Shapovalova
    • , Mio Nakanishi
    • , Deanna P. Porras
    • , Mohammed Almakadi
    • , Clinton J. V. Campbell
    • , Tony J. Collins
    •  & Mickie Bhatia
  2. Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8N 3Z5, Canada

    • Jennifer C. Reid
    • , Kyle R. Salci
    • , Lili Aslostovar
    • , Deanna P. Porras
    • , Mohammed Almakadi
    •  & Mickie Bhatia
  3. Central Animal Core Imaging and Transgenic Facilities, Central Animal Care Services, Rady Faculty of Health Sciences, University of Manitoba, 710 William Avenue, SR426 Winnipeg, Manitoba R3E 0Z3, Canada

    • Michael F. Jackson
  4. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario L8S 4L8, Canada

    • Catherine A. Ross
    • , Ronan Foley
    •  & Brian Leber
  5. Department of Medicine, Division of Hematology, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada

    • David S. Allan
    •  & Mitchell Sabloff
  6. Department of Medicine, Division of Hematology, Schulich School of Medicine, University of Western Ontario, London, Ontario N6A 3K7, Canada

    • Anargyros Xenocostas

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Contributions

A.L.B., J.C.R., K.R.S., L.A., Y.D.B., Z.S., M.N., D.P.P. and C.J.V.C. performed experiments. M.F.J. performed microCT imaging and analysis. Z.S. performed bioinformatic analyses. M.A. performed clinical analyses. T.J.C. wrote custom image analysis scripts. C.A.R., R.F., B.L., D.S.A., M.S. and A.X. provided critical patient samples and clinical expertise. A.L.B. and M.B. interpreted data and wrote the manuscript. M.B. directed the study.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Mickie Bhatia.

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https://doi.org/10.1038/ncb3625

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