A myeloid tumor suppressor role for NOL3

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 Nol3 (Nucleolar protein 3) in mice leads to an MPN resembling primary myelofibrosis (PMF). Nol3(-/-) MPN mice harbor an expanded Thy1(+)LSK stem cell population exhibiting increased cell cycling and a myelomonocytic differentiation bias. Molecularly, this phenotype is mediated by Nol3(-/-) -induced JAK-STAT activation and downstream activation of cyclin-depen-dent kinase 6 (Cdk6) and Myc. Nol3(-/-) MPN Thy1(+)LSK cells share significant molecular similarities with primary CD34(+) cells from PMF patients. NOL3 levels are decreased in CD34(+) cells from PMF patients, and the NOL3 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 NOL3 in the pathogenesis of myeloid malignancies.