A myeloid tumor suppressor role for .

Despite the identification of several oncogenic driver mutations leading to constitutive JAK-STAT activation, the cellular and molecular biology of myeloproliferative neoplasms (MPN) remains incompletely understood. Recent discoveries have identified underlying disease-modifying molecular aberrations contributing to disease initiation and progression. Here, we report that deletion of () in mice leads to an MPN resembling primary myelofibrosis (PMF). MPN mice harbor an expanded Thy1LSK stem cell population exhibiting increased cell cycling and a myelomonocytic differentiation bias. Molecularly, this phenotype is mediated by -induced JAK-STAT activation and downstream activation of () and MPN Thy1LSK cells share significant molecular similarities with primary CD34 cells from PMF patients. levels are decreased in CD34 cells from PMF patients, and the locus is deleted in a subset of patients with myeloid malignancies. Our results reveal a novel genetic PMF-like mouse model and identify a tumor suppressor role for in the pathogenesis of myeloid malignancies.