β-Arrestin2 mediates progression of murine primary myelofibrosis
Lindsay A.M. Rein, … , Richard T. Premont, Robert J. Lefkowitz
Lindsay A.M. Rein, … , Richard T. Premont, Robert J. Lefkowitz
Published December 21, 2017
Citation Information: JCI Insight. 2017;2(24):e98094. https://doi.org/10.1172/jci.insight.98094.
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Research Article Hematology Oncology

β-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. 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.

Authors

Lindsay A.M. Rein, James W. Wisler, Jihee Kim, Barbara Theriot, LiYin Huang, Trevor Price, Haeyoon Yang, Minyong Chen, Wei Chen, Dorothy Sipkins, Yuri Fedoriw, Julia K.L. Walker, Richard T. Premont, Robert J. Lefkowitz

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Figure 1

β-Arrestin2 is necessary for development of primary myelofibrosis in a murine disease model.

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β-Arrestin2 is necessary for development of primary myelofibrosis in a m...
WT, β-arrestin1–knockout (βarr1–/–), and β-arrestin2–knockout (βarr2–/–) KLS cells and a retroviral transduction system were used to model MPLW515L-mutant primary myelofibrosis (PMF). (A) Median survival of mice receiving MPLW515L-expressing βarr2–/– donor cells is longer compared with WT or βarr1–/– cell recipients by log-rank Mantel-Cox test (****P < 0.0001). (B) Spleen-to-body and liver-to-body ratios were lower in mice receiving βarr2–/– donor cells (****P < 0.0001, 1-way ANOVA). (C) White blood cells (WBCs) were lower over time in mice receiving βarr2–/– cells versus WT or βarr1–/– cells (****P < 0.0001 for time/row factor, P < 0.01 for interaction, P < 0.0001 WT vs. βarr2–/–, P < 0.0001 βarr1–/– vs. βarr2–/–). Platelets were lower in mice receiving βarr2–/– cells versus WT or βarr1–/– cells (****P < 0.0001 for time/row factor, P < 0.05 for interaction, P < 0.0001 WT vs. βarr2–/–, P < 0.0001 βarr1–/– vs. βarr2–/–). Hemoglobin was higher over time in mice receiving βarr2–/– cells versus WT or βarr1–/– cells (****P < 0.0001 for time/row factor, P < 0.0001 for interaction). Donor chimerism was lower over time in mice receiving βarr2–/– cells versus WT or βarr1–/– cells (****P < 0.0001 for time/row factor, P < 0.05 for interaction, P < 0.0001 WT vs. βarr2–/– and βarr1–/– vs. βarr2–/–). Two-way ANOVA was used for all analyses. No differences were noted in mice receiving WT vs. βarr1–/– donor cells for all secondary measures. WT, n = 11; βarr1–/–, n = 12; βarr2–/–, n = 16.