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

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.

Extracellular vesicles impose quiescence on residual hematopoietic stem cells in the leukemic niche

“…Intriguingly, HSC in the leukemic niche enter quiescence through an unidentified process, yet appear to retain their repopulation capacity upon subsequent re-transplantation [22]. We recently showed that AML-EV, including exosomes, are highly abundant in microRNA (miR)-150 and miR-155, which both target the transcription factor c-Myb to suppress HSPC clonogenicity [17,[27][28][29]. We recently showed that AML-EV, including exosomes, are highly abundant in microRNA (miR)-150 and miR-155, which both target the transcription factor c-Myb to suppress HSPC clonogenicity [17,[27][28][29].…”

Rab27-Dependent Exosome Production Inhibits Chronic Inflammation and Enables Acute Responses to Inflammatory Stimuli

“…Such effects have been observed both systemically and in specific tissues, including those that make up the central nervous system (16). Additionally, miR-155 can also be transferred from acute myeloid leukemia (AML) cells to healthy blood cells, resulting in the suppression of c-MYB and compromised hematopoiesis in the context of cancer (17). These examples clearly demonstrate that miRNAs contained within exosomes are involved in the communication between immune and other hematopoietic cells, during both physiological and pathological situations.…”

Extracellular Vesicles in Hematological Malignancies: From Biology to Therapy

“…In addition, AML derived Exo suppressed residual HSPC functions by “decreasing” clonogenicity and by reprogramming stroma, respectively [81,82]. Recently, BM-AML-MVs promoted the survival of healthy hematopoietic stem cells (HSCs) without changing their immature phenotype and their ability to form colonies, but inducing leukemic-like functional characteristics, such as miR21 and miR29 over-expression [83].…”

“…Its amount was directly correlated with white blood count cells and complex karyotypes and could be further investigated as a biomarker in AML patients. Interestingly, in an AML xenograft mouse model, Exo miR155 and other miRNAs were indicative of AML presence, thus suggesting their potential use for minimal residual disease detection [81,152]. …”