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J Exp Med. 2017 Mar 6;214(3):753-771. doi: 10.1084/jem.20162089. Epub 2017 Feb 23.

A myeloid tumor suppressor role for NOL3.

Author information

1
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461.
2
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, OH 44195.
3
Leukemia Program, Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH 44195.
4
Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461.
5
Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461.
6
Department of Medicine, Albert Einstein College of Medicine-Montefiore Medical Center, Bronx, NY 10461.
7
Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461.
8
Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461.
9
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461 ulrich.steidl@einstein.yu.edu.

Abstract

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 MycNol3-/- 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.

PMID:
28232469
PMCID:
PMC5339683
DOI:
10.1084/jem.20162089
[Indexed for MEDLINE]
Free PMC Article

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