Research ArticleCANCER EXOSOMES

AML suppresses hematopoiesis by releasing exosomes that contain microRNAs targeting c-MYB

Sci. Signal.  06 Sep 2016:
Vol. 9, Issue 444, pp. ra88
DOI: 10.1126/scisignal.aaf2797

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AML dispatches micromanagers

In patients with acute myeloid leukemia (AML), the production of healthy blood cells from hematopoietic stem cells in the bone marrow (a process called hematopoiesis) is suppressed, prompting the need for bone marrow transplants. AML cells shed extracellular vesicles called exosomes that contain molecules that suppress hematopoiesis by reprogramming the stem cell niche. Hornick et al. discovered another way that AML exosomes block this critical process by delivering microRNAs to hematopoietic stem cells. The AML-derived exosomes contained two mature microRNAs that target the mRNA encoding c-MYB, a transcription factor involved in hematopoiesis. Other targets of these AML-derived exosomal microRNAs reveal interconnected networks targeting transcripts that produce proteins that control the cell cycle. The findings suggest that disrupting this mode of intercellular communication might enhance hematopoiesis in AML patients.

Abstract

Exosomes are paracrine regulators of the tumor microenvironment and contain complex cargo. We previously reported that exosomes released from acute myeloid leukemia (AML) cells can suppress residual hematopoietic stem and progenitor cell (HSPC) function indirectly through stromal reprogramming of niche retention factors. We found that the systemic loss of hematopoietic function is also in part a consequence of AML exosome–directed microRNA (miRNA) trafficking to HSPCs. Exosomes isolated from cultured AML or the plasma from mice bearing AML xenografts exhibited enrichment of miR-150 and miR-155. HSPCs cocultured with either of these exosomes exhibited impaired clonogenicity, through the miR-150– and miR-155–mediated suppression of the translation of transcripts encoding c-MYB, a transcription factor involved in HSPC differentiation and proliferation. To discover additional miRNA targets, we captured miR-155 and its target transcripts by coimmunoprecipitation with an attenuated RNA-induced silencing complex (RISC)–trap, followed by high-throughput sequencing. This approach identified known and previously unknown miR-155 target transcripts. Integration of the miR-155 targets with information from the protein interaction database STRING revealed proteins indirectly affected by AML exosome–derived miRNA. Our findings indicate a direct effect of AML exosomes on HSPCs that, through a stroma-independent mechanism, compromises hematopoiesis. Furthermore, combining miRNA target data with protein-protein interaction data may be a broadly applicable strategy to define the effects of exosome-mediated trafficking of regulatory molecules within the tumor microenvironment.

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