A myeloid tumor suppressor role for NOL3

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

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Primary Myelofibrosis
Neoplasms
Nuclear Proteins
Cyclin-Dependent Kinase 6
Cell Biology
Disease Progression
Molecular Biology
Stem Cells
Phenotype
Mutation
Population

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

A myeloid tumor suppressor role for NOL3. / Stanley, Robert F.; Piszczatowski, Richard T.; Bartholdy, Boris A.; Mitchell, Kelly; McKimpson, Wendy M.; Narayanagari, Swathi-Rao; Walter, Dagmar; Todorova, Tihomira I.; Hirsch, Cassandra; Makishima, Hideki; Will, Britta; McMahon, Christine; Gritsman, Kira; Maciejewski, Jaroslaw P.; Kitsis, Richard N.; Steidl, Ulrich G.

In: The Journal of experimental medicine, Vol. 214, No. 3, 06.03.2017, p. 753-771.

Research output: Contribution to journalArticle

Stanley, RF, Piszczatowski, RT, Bartholdy, BA, Mitchell, K, McKimpson, WM, Narayanagari, S-R, Walter, D, Todorova, TI, Hirsch, C, Makishima, H, Will, B, McMahon, C, Gritsman, K, Maciejewski, JP, Kitsis, RN & Steidl, UG 2017, 'A myeloid tumor suppressor role for NOL3', The Journal of experimental medicine, vol. 214, no. 3, pp. 753-771. https://doi.org/10.1084/jem.20162089
Stanley, Robert F. ; Piszczatowski, Richard T. ; Bartholdy, Boris A. ; Mitchell, Kelly ; McKimpson, Wendy M. ; Narayanagari, Swathi-Rao ; Walter, Dagmar ; Todorova, Tihomira I. ; Hirsch, Cassandra ; Makishima, Hideki ; Will, Britta ; McMahon, Christine ; Gritsman, Kira ; Maciejewski, Jaroslaw P. ; Kitsis, Richard N. ; Steidl, Ulrich G. / A myeloid tumor suppressor role for NOL3. In: The Journal of experimental medicine. 2017 ; Vol. 214, No. 3. pp. 753-771.
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