?-Arrestin2 mediates progression of murine primary myelofibrosis.

ABSTRACT: Primary myelofibrosis is a myeloproliferative neoplasm associated with significant morbidity and mortality, for which effective therapies are lacking. ?-Arrestins are multifunctional adaptor proteins involved in developmental signaling pathways. One isoform, ?-arrestin2 (?arr2), has been implicated in initiation and progression of chronic myeloid leukemia, another myeloproliferative neoplasm closely related to primary myelofibrosis. Accordingly, we investigated the relationship between ?arr2 and primary myelofibrosis. In a murine model of MPLW515L-mutant primary myelofibrosis, mice transplanted with donor ?arr2-knockout (?arr2-/-) hematopoietic stem cells infected with MPL-mutant retrovirus did not develop myelofibrosis, whereas controls uniformly succumbed to disease. Although transplanted ?arr2-/- cells homed properly to marrow, they did not repopulate long-term due to increased apoptosis and decreased self-renewal of ?arr2-/- cells. In order to assess the effect of acute loss of ?arr2 in established primary myelofibrosis in vivo, we utilized a tamoxifen-induced Cre-conditional ?arr2-knockout mouse. Mice that received Cre (+) donor cells and developed myelofibrosis had significantly improved survival compared with controls. These data indicate that lack of antiapoptotic ?arr2 mediates marrow failure of murine hematopoietic stem cells overexpressing MPLW515L. They also indicate that ?arr2 is necessary for progression of primary myelofibrosis, suggesting that it may serve as a novel therapeutic target in this disease.

SUBMITTER: Rein LA 

PROVIDER: S-EPMC5752278 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature