A myeloid tumor suppressor role for NOL3.
Robert F StanleyRichard T PiszczatowskiBoris BartholdyKelly MitchellWendy M McKimpsonSwathi NarayanagariDagmar WalterTihomira I TodorovaCassandra M HirschHideki MakishimaBritta WillChristine McMahonKira GritsmanJaroslaw P MaciejewskiRichard N KitsisUlrich SteidlPublished in: The Journal of experimental medicine (2017)
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.
Keyphrases
- end stage renal disease
- stem cells
- newly diagnosed
- chronic kidney disease
- ejection fraction
- bone marrow
- acute myeloid leukemia
- dendritic cells
- prognostic factors
- single cell
- induced apoptosis
- genome wide
- cell cycle
- type diabetes
- single molecule
- dna methylation
- oxidative stress
- copy number
- signaling pathway
- skeletal muscle
- small molecule
- binding protein
- cell proliferation
- amino acid