title: MERIT40 deficiency expands hematopoietic stem cell pools by regulating thrombopoietin receptor signaling.
abstract: Hematopoietic stem cell (HSC) self-renewal and multilineage reconstitution are controlled by positive and negative signaling cues with perturbations leading to disease. Lnk is an essential signaling adaptor protein that dampens signaling by the cytokine thrombopoietin (Tpo) to limit HSC expansion. Here, we show that MERIT40 (Mediator of RAP80 Interactions and Targeting 40 kDa [M40]), a core subunit of an Lnk-associated Lys63 deubiquitinating (DUB) complex, attenuates HSC expansion. M40 deficiency increases the size of phenotypic and functional HSC pools. M40(-/-) HSCs are more resistant to cytoablative stress, and exhibit superior repopulating ability and self-renewal upon serial transplantation. M40(-/-) HSCs display increased quiescence and decelerated cell cycle kinetics accompanied by downregulation of gene sets associated with cell division. Mechanistically, M40 deficiency triggers hypersensitivity to Tpo stimulation and the stem cell phenotypes are abrogated on a background null for the Tpo receptor Mpl. These results establish M40-containing DUB complexes as novel HSC regulators of HSC expansion, implicate Lys63 ubiquitination in HSC signaling, and point to DUB-specific inhibitors as reagents to expand stem cell populations.
authors: Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA; and Department of Pediatrics and.
authors: Krasimira
authors: K
authors: Rozenova
authors: Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA; and Department of Pediatrics and.
authors: Jing
authors: J
authors: Jiang
authors: Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA; and.
authors: Ryan
authors: R
authors: Donaghy
authors: Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
authors: Bernadette
authors: B
authors: Aressy
authors: Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
authors: Roger A
authors: RA
authors: Greenberg
authors: Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA; and Department of Pediatrics and.
authors: Wei
authors: W
authors: Tong
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002453:Cell Cycle; D049109:Cell Proliferation; D003114:Colony-Forming Units Assay; D005260:Female; D005472:Fluorouracil / Q000633:toxicity; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053628:Receptors, Thrombopoietin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013312:Stress, Physiological; D013926:Thrombopoietin / Q000378:metabolism; D064570:Ubiquitin-Specific Proteases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000598769:MERIT40 protein, mouse; C481270:Mpl protein, mouse; D053628:Receptors, Thrombopoietin; D013926:Thrombopoietin; D064570:Ubiquitin-Specific Proteases; D005472:Fluorouracil
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