Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 214, Issue 3, Pages 753-771Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20162089
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Funding
- NYSTEM grant [C029154]
- National Institutes of Health (NIH) [R01CA166429, R01CA196973]
- MSTP training grant [T32GM007288]
- National Heart, Lung, and Blood Institute Fellowship [F30HL122085]
- NIH Cellular and Molecular Biology and Genetics Training Grant [T32GM007491]
- Dr. Gerald and Myra Dorros Chair in Cardiovascular Disease
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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-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.
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