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.
- Submitted: 11 December 2016
- Revision received 4 January 2017
- Accepted: 5 January 2017
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).