title: A myeloid tumor suppressor role forNOL3.
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 ofNol3(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 byNol3-/--induced JAK-STAT activation and downstream activation ofcyclin-dependent kinase 6(Cdk6) andMycNol3-/-MPN Thy1+LSK cells share significant molecular similarities with primary CD34+cells from PMF patients.NOL3levels are decreased in CD34+cells from PMF patients, and theNOL3locus 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 forNOL3in the pathogenesis of myeloid malignancies.
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461.
authors.forename: Robert F
authors.identifier: 0000-0003-3643-8592
authors.initials: RF
authors.lastname: Stanley
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461.
authors.forename: Richard T
authors.identifier: 0000-0002-1250-683X
authors.initials: RT
authors.lastname: Piszczatowski
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461.
authors.forename: Boris
authors.initials: B
authors.lastname: Bartholdy
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461.
authors.forename: Kelly
authors.initials: K
authors.lastname: Mitchell
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461.
authors.forename: Wendy M
authors.initials: WM
authors.lastname: McKimpson
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461.
authors.forename: Swathi
authors.initials: S
authors.lastname: Narayanagari
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Walter
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461.
authors.forename: Tihomira I
authors.initials: TI
authors.lastname: Todorova
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, OH 44195.|Leukemia Program, Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH 44195.
authors.forename: Cassandra
authors.identifier: 0000-0002-2174-6560
authors.initials: C
authors.lastname: Hirsch
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, OH 44195.|Leukemia Program, Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH 44195.
authors.forename: Hideki
authors.initials: H
authors.lastname: Makishima
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461.|Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461.|Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461.|Department of Medicine, Albert Einstein College of Medicine-Montefiore Medical Center, Bronx, NY 10461.
authors.forename: Britta
authors.initials: B
authors.lastname: Will
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461.
authors.forename: Christine
authors.initials: C
authors.lastname: McMahon
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461.|Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461.|Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461.|Department of Medicine, Albert Einstein College of Medicine-Montefiore Medical Center, Bronx, NY 10461.
authors.forename: Kira
authors.initials: K
authors.lastname: Gritsman
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, OH 44195.|Leukemia Program, Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH 44195.
authors.forename: Jaroslaw P
authors.initials: JP
authors.lastname: Maciejewski
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461.|Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461.|Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461.|Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461.|Department of Medicine, Albert Einstein College of Medicine-Montefiore Medical Center, Bronx, NY 10461.
authors.forename: Richard N
authors.initials: RN
authors.lastname: Kitsis
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461 ulrich.steidl@einstein.yu.edu.|Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461.|Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461.|Department of Medicine, Albert Einstein College of Medicine-Montefiore Medical Center, Bronx, NY 10461.
authors.forename: Ulrich
authors.identifier: 0000-0002-9458-1795
authors.initials: U
authors.lastname: Steidl
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D006411:Hematopoiesis, Extramedullary / Q000502:physiology; D006801:Humans; D053612:Janus Kinases / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000235:genetics / Q000502:physiology*; D055728:Primary Myelofibrosis / Q000209:etiology; D050796:STAT3 Transcription Factor / Q000502:physiology; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D009124:Muscle Proteins; C112246:NOL3 protein, human; C491787:Nol3 protein, mouse; D050796:STAT3 Transcription Factor; D025521:Tumor Suppressor Proteins; D053612:Janus Kinases