AML suppresses hematopoiesis by releasing exosomes that contain microRNAs targeting c-MYB.
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.
Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA. Pediatric Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA. Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR 97239, USA.
Noah I
NI
Hornick
Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA. Pediatric Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA. Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR 97239, USA.
Ben
B
Doron
Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA. Pediatric Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA. Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR 97239, USA.
Sherif
S
Abdelhamed
Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA. Pediatric Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA. Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
Jianya
J
Huan
Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA. Integrated Genomics Laboratory, Oregon Health & Science University, Portland, OR 97239, USA.
Christina A
CA
Harrington
Department of Biology, State University of New York, Brockport, NY 14420, USA. Vollum Institute, Oregon Health & Science University, Portland, OR 97239, USA. The College at Brockport, State University of New York, Brockport, NY 14420, USA.
Rongkun
R
Shen
Vollum Institute, Oregon Health & Science University, Portland, OR 97239, USA.
Xiaolu A
XA
Cambronne
Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA. Pediatric Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA. Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR 97239, USA.
Santhosh
S
Chakkaramakkil Verghese
Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA. Pediatric Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA. Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR 97239, USA. Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA. kurrepe@ohsu.edu.
Peter
P
Kurre
D000818:Animals; D055354:Exosomes / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018922:HL-60 Cells; D006410:Hematopoiesis; D064593:Heterografts; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D020598:Proto-Oncogene Proteins c-myb / Q000096:biosynthesis* / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism*
D035683:MicroRNAs; D020598:Proto-Oncogene Proteins c-myb; D012334:RNA, Neoplasm; C533097:MIR150, human; C524942:MIRN155 microRNA, human