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

SUBMITTER: Rozenova K 

PROVIDER: S-EPMC4357581 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature