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

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 broad...

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Vydáno v:	Leukemia Ročník 29; číslo 12; s. 2285 - 2295
Hlavní autoři:	Huan, J, Hornick, N I, Goloviznina, N A, Kamimae- Lanning, A N, David, L L, Wilmarth, P A, Mori, T, Chevillet, J R, Narla, A, Roberts, C T, Loriaux, M M, Chang, B H, Kurre, P
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 01.12.2015 Nature Publishing Group
Témata:	13/100 13/106 13/21 13/31 13/51 14/35 38/77 38/79 38/90 631/250/1620/1342 631/378/548/2590 631/67/1990/283/1897 64/60 692/699/1541/1990/283/1897 82/51 82/79 Acute myeloid leukemia Animals Biosynthesis Bone marrow Bone Marrow - physiopathology c-Kit protein c-Myb protein Cancer Research Cell Movement Cells (biology) Cellular proteins Cellular signal transduction Critical Care Medicine CXCL12 protein CXCR4 protein Exosomes Exosomes - physiology Experiments Gene silencing Genetic aspects Genetic regulation Health aspects Hematology Hematopoiesis Hematopoietic stem cells Hematopoietic Stem Cells - physiology HL-60 Cells Humans Intensive Internal Medicine Leukemia Leukemia, Myeloid, Acute - pathology Leukemia, Myeloid, Acute - physiopathology Medical research Medicine Medicine & Public Health Mice Mice, Inbred C57BL Myeloid leukemia Neovascularization Oncology original-article Paracrine signalling Pediatrics Progenitor cells Proteomics Ribonucleic acid RNA Science Stem cells Stromal cells Transcription factors Tumor cell lines Xenografts Xenotransplantation United States Oregon United States > US
ISSN:	0887-6924, 1476-5551
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Popis
Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	0887-6924 1476-5551
DOI:	10.1038/leu.2015.163