Format

Send to

Choose Destination
JCI Insight. 2017 Dec 21;2(24). pii: 98094. doi: 10.1172/jci.insight.98094. [Epub ahead of print]

β-Arrestin2 mediates progression of murine primary myelofibrosis.

Author information

1
Division of Hematologic Malignancies and Cellular Therapy.
2
Division of Cardiology.
3
Department of Medicine, and.
4
Division of Gastroenterology, Duke University, Durham, North Carolina, USA.
5
Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
6
Duke University School of Nursing and.
7
Department of Medicine, Department of Biochemistry, and Howard Hughes Medical Institute, Duke University, Durham, North Carolina, USA.

Abstract

Primary myelofibrosis is a myeloproliferative neoplasm associated with significant morbidity and mortality, for which effective therapies are lacking. β-Arrestins are multifunctional adaptor proteins involved in developmental signaling pathways. One isoform, β-arrestin2 (βarr2), 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 βarr2 and primary myelofibrosis. In a murine model of MPLW515L-mutant primary myelofibrosis, mice transplanted with donor βarr2-knockout (βarr2-/-) hematopoietic stem cells infected with MPL-mutant retrovirus did not develop myelofibrosis, whereas controls uniformly succumbed to disease. Although transplanted βarr2-/- cells homed properly to marrow, they did not repopulate long-term due to increased apoptosis and decreased self-renewal of βarr2-/- cells. In order to assess the effect of acute loss of βarr2 in established primary myelofibrosis in vivo, we utilized a tamoxifen-induced Cre-conditional βarr2-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 βarr2 mediates marrow failure of murine hematopoietic stem cells overexpressing MPLW515L. They also indicate that βarr2 is necessary for progression of primary myelofibrosis, suggesting that it may serve as a novel therapeutic target in this disease.

KEYWORDS:

Apoptosis; Hematology; Hematopoietic stem cells; Leukemias; Oncology

Supplemental Content

Full text links

Icon for American Society for Clinical Investigation Icon for PubMed Central
Loading ...
Support Center