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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-dependent 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.

A myeloid tumor suppressor role for NOL3