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2017 ; 214
(3
): 753-771
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A myeloid tumor suppressor role for NOL3
#MMPMID28232469
Stanley RF
; Piszczatowski RT
; Bartholdy B
; Mitchell K
; McKimpson WM
; Narayanagari S
; Walter D
; Todorova TI
; Hirsch C
; Makishima H
; Will B
; McMahon C
; Gritsman K
; Maciejewski JP
; Kitsis RN
; Steidl U
J Exp Med
2017[Mar]; 214
(3
): 753-771
PMID28232469
show ga
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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