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Acute myeloid leukemia

Transmissible ER stress reconfigures the AML bone marrow compartment

Leukemia volume 33, pages 918–930 (2019)Cite this article

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Abstract

Successive adaptation of the bone marrow (BM) from homeostatic hematopoietic microenvironment to a self-reinforcing niche is an integral aspect of leukemogenesis. Yet, the cellular mechanisms underlying these functional alterations remain to be defined. Here, we found that AML incursion precipitates compartmental endoplasmic reticulum (ER) stress and an unfolded protein response (UPR) in both leukemia and stromal cells. We observed that extracellular vesicles (EV) transmit ER stress in vivo from the AML xenograft to BM stroma, whereby the upregulation of core UPR components drives subsequent osteolineage differentiation of mesenchymal stem cells (MSC). Finally, we show that the underlying mechanism involves quantitative incorporation and cell–cell transfer of Bone Morphogenic Protein 2 (BMP2), a potent osteogenic signal, by AML-EVs. Corroborative studies in AML patient samples support the translational relevance of AML-EVs as a platform for BMP trafficking and source of compartmental crosstalk. Transmissible ER stress was previously identified as a source of chemoresistance in solid tumor models, and this work reveals a role in remodeling the BM niche in AML.

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Acknowledgements

We are indebted to staff in the Department of Comparative Medicine for excellent veterinary care, the technicians at the OHSU Flow Cytometry core, and acknowledge contributions by all members of the labs. These studies were funded in part by: Hyundai Hope on Wheels (PK), Max Blue Butterfly Campaign (PK), R01-CA164024 (TMH), and Hyundai Hope on Wheels grant (TMH).

Author contributions

BD conceived the study, designed and performed the experiments, analyzed data, interpreted the results, and wrote the paper; SA performed xenograft studies, intrafemoral injections, and helped with experiments; JTB performed microscopy and in vitro experiments, analyzed the data, generated figures and edited the manuscript; SKH organized, generated and interpreted patient data, and edited the manuscript; TMH consented patients, supervised patient data collection and experiments, interpreted patient data, and edited the manuscript; PK conceived the study, designed the experiments, interpreted the results, wrote the paper, and oversaw the research project.

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Authors and Affiliations

  1. Department of Pediatrics, Pediatric Blood & Cancer Biology Program, Papé Family Pediatric Research Institute, Portland, OR, USA

    Ben Doron, Sherif Abdelhamed, John T. Butler & Peter Kurre

  2. OHSU Knight Cancer Institute, Portland, OR, USA

    Ben Doron, Sherif Abdelhamed, John T. Butler & Peter Kurre

  3. Department of Biomedical Engineering, Portland, OR, USA

    Ben Doron, Sherif Abdelhamed, John T. Butler & Peter Kurre

  4. Oregon Health & Science University, Portland, OR, USA

    John T. Butler

  5. Texas Children’s Cancer and Hematology Centers, Baylor College of Medicine, Houston, TX, USA

    Saman K. Hashmi & Terzah M. Horton

  6. Division of Hematology, The Children’s Hospital of Philadelphia, 3501 Civic Center Boulevard, ARC 302, Philadelphia, 19104, PA, USA

    Peter Kurre

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Correspondence to Peter Kurre.

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Doron, B., Abdelhamed, S., Butler, J.T. et al. Transmissible ER stress reconfigures the AML bone marrow compartment. Leukemia 33, 918–930 (2019). https://doi.org/10.1038/s41375-018-0254-2

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