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Acute myeloid leukemia

Coordinate regulation of residual bone marrow function by paracrine trafficking of AML exosomes

Leukemia volume 29, pages 2285–2295 (2015)Cite this article

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Abstract

We recently demonstrated that acute myeloid leukemia (AML) cell lines and patient-derived blasts release exosomes that carry RNA and protein; following an in vitro transfer, AML exosomes produce proangiogenic changes in bystander cells. We reasoned that paracrine exosome trafficking may have a broader role in shaping the leukemic niche. In a series of in vitro studies and murine xenografts, we demonstrate that AML exosomes downregulate critical retention factors (Scf, Cxcl12) in stromal cells, leading to hematopoietic stem and progenitor cell (HSPC) mobilization from the bone marrow. Exosome trafficking also regulates HSPC directly, and we demonstrate declining clonogenicity, loss of CXCR4 and c-Kit expression, and the consistent repression of several hematopoietic transcription factors, including c-Myb, Cebp-β and Hoxa-9. Additional experiments using a model of extramedullary AML or direct intrafemoral injection of purified exosomes reveal that the erosion of HSPC function can occur independent of direct cell–cell contact with leukemia cells. Finally, using a novel multiplex proteomics technique, we identified candidate pathways involved in the direct exosome-mediated modulation of HSPC function. In aggregate, this work suggests that AML exosomes participate in the suppression of residual hematopoietic function that precedes widespread leukemic invasion of the bone marrow directly and indirectly via stromal components.

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Acknowledgements

This manuscript is dedicated to the late Dr Zili Zhang, a thoughtful scientist, inspired colleague and, above all, a good friend. We acknowledge the assistance of Dr Muneesh Tewari, Dr Ashok Reddy, John Klimek, Rajani Kaimal, Aurelie Snyder and Jennifer Wherley. Studies were supported in part by the St. Baldrick’s Foundation (PK), the Hyundai Hope on Wheels Foundation (PK), NIH/NIAID T32 grant (5T32AI78903-5) (NH), NIH core grants P30EY10572 and P30CA069533 and a Canary Foundation/American Cancer Society (ACS) Postdoctoral Fellowship (PFTED-09-249-01-SEID) with support by the Hillcrest Committee of Southern Oregon and the ACS Great West Division (JRC).

Author contributions

JH designed and performed experiments, interpreted data and prepared the manuscript; NH designed and performed experiments and interpreted data; NG performed experiments; ANK interpreted data and edited the manuscript; LLD interpreted data and edited the manuscript; PAW performed experiments and interpreted data; TM interpreted data and edited the manuscript; JRC performed experiments; AN performed experiments and interpreted data; CR interpreted data and edited the manuscript; ML interpreted data and edited the manuscript; BHC interpreted data and edited the manuscript; PK designed experiments, interpreted data and edited the manuscript.

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Authors and Affiliations

  1. Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA

    J Huan, N I Hornick, N A Goloviznina, A N Kamimae- Lanning, C T Roberts Jr, B H Chang & P Kurre

  2. Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR, USA

    J Huan, N I Hornick, N A Goloviznina, A N Kamimae- Lanning & P Kurre

  3. Oregon Stem Cell Center, Oregon Health & Science University, Portland, OR, USA

    J Huan, N I Hornick, N A Goloviznina, A N Kamimae- Lanning & P Kurre

  4. Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, OR, USA

    L L David & P A Wilmarth

  5. Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA

    T Mori, M M Loriaux, B H Chang & P Kurre

  6. Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    J R Chevillet

  7. Division of Hematology/Oncology, Stanford University, Palo Alto, CA, USA

    A Narla

  8. Department of Medicine, Oregon Health & Science University, Portland, OR, USA

    C T Roberts Jr & M M Loriaux

  9. Oregon National Primate Research Center, Beaverton, OR, USA

    C T Roberts Jr

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Huan, J., Hornick, N., Goloviznina, N. et al. Coordinate regulation of residual bone marrow function by paracrine trafficking of AML exosomes. Leukemia 29, 2285–2295 (2015). https://doi.org/10.1038/leu.2015.163

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