title: Coordinate regulation of residual bone marrow function by paracrine trafficking of AML exosomes.
abstract: 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.
authors.affiliation: Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA.|Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR, USA.|Oregon Stem Cell Center, Oregon Health & Science University, Portland, OR, USA.
authors.forename: J
authors.initials: J
authors.lastname: Huan
authors.affiliation: Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA.|Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR, USA.|Oregon Stem Cell Center, Oregon Health & Science University, Portland, OR, USA.
authors.forename: N I
authors.initials: NI
authors.lastname: Hornick
authors.affiliation: Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA.|Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR, USA.|Oregon Stem Cell Center, Oregon Health & Science University, Portland, OR, USA.
authors.forename: N A
authors.initials: NA
authors.lastname: Goloviznina
authors.affiliation: Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA.|Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR, USA.|Oregon Stem Cell Center, Oregon Health & Science University, Portland, OR, USA.
authors.forename: A N
authors.initials: AN
authors.lastname: Kamimae-Lanning
authors.affiliation: Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, OR, USA.
authors.forename: L L
authors.initials: LL
authors.lastname: David
authors.affiliation: Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, OR, USA.
authors.forename: P A
authors.initials: PA
authors.lastname: Wilmarth
authors.affiliation: Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
authors.forename: T
authors.initials: T
authors.lastname: Mori
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Chevillet
authors.affiliation: Division of Hematology/Oncology, Stanford University, Palo Alto, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Narla
authors.affiliation: Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA.|Department of Medicine, Oregon Health & Science University, Portland, OR, USA.|Oregon National Primate Research Center, Beaverton, OR, USA.
authors.forename: C T
authors.initials: CT
authors.lastname: Roberts
authors.affiliation: Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.|Department of Medicine, Oregon Health & Science University, Portland, OR, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Loriaux
authors.affiliation: Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA.|Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
authors.forename: B H
authors.initials: BH
authors.lastname: Chang
authors.affiliation: Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA.|Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR, USA.|Oregon Stem Cell Center, Oregon Health & Science University, Portland, OR, USA.|Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
authors.forename: P
authors.initials: P
authors.lastname: Kurre
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000503:physiopathology*; D002465:Cell Movement; D055354:Exosomes / Q000502:physiology*; D018922:HL-60 Cells; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000502:physiology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL