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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Veröffentlicht in:Leukemia Jg. 29; H. 12; S. 2285 - 2295
Hauptverfasser: 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
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 01.12.2015
Nature Publishing Group
Schlagworte:
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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
Online-Zugang:Volltext
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Zusammenfassung: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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:0887-6924
1476-5551
DOI:10.1038/leu.2015.163