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

doi:10.1084/jem.20162089

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

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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 language	English (US)
Pages (from-to)	753-771
Number of pages	19
Journal	The Journal of experimental medicine
Volume	214
Issue number	3
DOIs	https://doi.org/10.1084/jem.20162089
State	Published - Mar 6 2017

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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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

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title = "A myeloid tumor suppressor role for NOL3",

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.",

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

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doi = "10.1084/jem.20162089",

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AU - Piszczatowski, Richard T.

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AU - Narayanagari, Swathi

AU - Walter, Dagmar

AU - Todorova, Tihomira I.

AU - Hirsch, Cassandra

AU - Makishima, Hideki

AU - Will, Britta

AU - McMahon, Christine

AU - Gritsman, Kira

AU - Maciejewski, Jaroslaw P.

AU - Kitsis, Richard N.

AU - Steidl, Ulrich

PY - 2017/3/6

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N2 - 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.

AB - 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.

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A myeloid tumor suppressor role for NOL3

Abstract

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