Journal
LEUKEMIA
Volume 29, Issue 12, Pages 2285-2295Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2015.163
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Funding
- St. Baldrick's Foundation
- Hyundai Hope on Wheels Foundation
- NIH/NIAID T32 grant [5T32AI78903-5]
- NIH [P30EY10572, P30CA069533]
- Canary Foundation/American Cancer Society (ACS) [PFTED-09-249-01-SEID]
- Hillcrest Committee of Southern Oregon
- ACS Great West Division
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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-beta 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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