A myeloid tumor suppressor role for NOL3

Robert F. Stanley, Richard T. Piszczatowski, Boris Bartholdy, Kelly Mitchell, Wendy M. McKimpson, Swathi Narayanagari, Dagmar Walter, Tihomira I. Todorova, Cassandra Hirsch, Hideki Makishima, Britta Will, Christine McMahon, Kira Gritsman, Jaroslaw P. Maciejewski, Richard N. Kitsis, Ulrich Steidl

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)753-771
Number of pages19
JournalThe Journal of experimental medicine
Volume214
Issue number3
DOIs
StatePublished - Mar 6 2017

    Fingerprint

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Stanley, R. F., Piszczatowski, R. T., Bartholdy, B., Mitchell, K., McKimpson, W. M., Narayanagari, S., Walter, D., Todorova, T. I., Hirsch, C., Makishima, H., Will, B., McMahon, C., Gritsman, K., Maciejewski, J. P., Kitsis, R. N., & Steidl, U. (2017). A myeloid tumor suppressor role for NOL3. The Journal of experimental medicine, 214(3), 753-771. https://doi.org/10.1084/jem.20162089