ABSTRACT
Primary myelofibrosis is a myeloproliferative neoplasm associated with significant morbidity and mortality, for which effective therapies are lacking. ß-Arrestins are multifunctional adaptor proteins involved in developmental signaling pathways. One isoform, ß-arrestin2 (ßarr2), 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 ßarr2 and primary myelofibrosis. In a murine model of MPLW515L-mutant primary myelofibrosis, mice transplanted with donor ßarr2-knockout (ßarr2-/-) hematopoietic stem cells infected with MPL-mutant retrovirus did not develop myelofibrosis, whereas controls uniformly succumbed to disease. Although transplanted ßarr2-/- cells homed properly to marrow, they did not repopulate long-term due to increased apoptosis and decreased self-renewal of ßarr2-/- cells. In order to assess the effect of acute loss of ßarr2 in established primary myelofibrosis in vivo, we utilized a tamoxifen-induced Cre-conditional ßarr2-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 ßarr2 mediates marrow failure of murine hematopoietic stem cells overexpressing MPLW515L. They also indicate that ßarr2 is necessary for progression of primary myelofibrosis, suggesting that it may serve as a novel therapeutic target in this disease.
Subject(s)
Primary Myelofibrosis/metabolism , beta-Arrestin 2/physiology , Animals , Apoptosis/physiology , Bone Marrow/pathology , Cell Proliferation/physiology , Disease Models, Animal , Disease Progression , Graft Survival/physiology , Hematopoietic Stem Cell Transplantation/methods , Hematopoietic Stem Cells/metabolism , Male , Mice, Knockout , Primary Myelofibrosis/chemically induced , Primary Myelofibrosis/pathology , Tamoxifen , beta-Arrestin 2/deficiency , beta-Arrestin 2/geneticsABSTRACT
Minimal residual disease (MRD) is a complex topic that has been studied extensively in hematologic malignancies given its clinical implications related to prognosis. However, methods to monitor and treat MRD, especially after stem cell transplantation, are not well defined and vary in different disease processes. Alternative transplant strategies, such as reduced-intensity conditioning, have altered the way we assess and address MRD after transplantation. Development of new diagnostic tools have allowed for higher sensitivity and specificity of testing. Both targeted chemotherapeutic agents and immunotherapies have been developed to treat MRD in hopes of improving patient outcomes. This article aims to address ways to define and manipulate MRD specifically after stem cell transplantation.
