A Murine Model of Chronic Lymphocytic Leukemia Based on B Cell-Restricted Expression of Sf3b1 Mutation and Atm Deletion.
Adenine
/ analogs & derivatives
Agammaglobulinaemia Tyrosine Kinase
/ antagonists & inhibitors
Alternative Splicing
Animals
Antineoplastic Agents
/ pharmacology
Ataxia Telangiectasia Mutated Proteins
/ deficiency
B-Lymphocytes
/ drug effects
Cellular Senescence
/ drug effects
DNA Damage
Gene Deletion
Genetic Predisposition to Disease
Genomic Instability
Humans
Leukemia, Lymphocytic, Chronic, B-Cell
/ drug therapy
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Knockout
Mice, Mutant Strains
Mutation
Neoplasms, Experimental
/ drug therapy
Phenotype
Phosphoproteins
/ genetics
Piperidines
Protein Kinase Inhibitors
/ pharmacology
Pyrazoles
/ pharmacology
Pyrimidines
/ pharmacology
RNA Splicing Factors
/ genetics
Receptors, Antigen, B-Cell
/ immunology
Signal Transduction
Tumor Cells, Cultured
ATM
BCR signaling
CLL
SF3B1
murine model
Journal
Cancer cell
ISSN: 1878-3686
Titre abrégé: Cancer Cell
Pays: United States
ID NLM: 101130617
Informations de publication
Date de publication:
11 02 2019
11 02 2019
Historique:
received:
18
05
2018
revised:
24
10
2018
accepted:
28
12
2018
pubmed:
5
2
2019
medline:
18
12
2019
entrez:
5
2
2019
Statut:
ppublish
Résumé
SF3B1 is recurrently mutated in chronic lymphocytic leukemia (CLL), but its role in the pathogenesis of CLL remains elusive. Here, we show that conditional expression of Sf3b1-K700E mutation in mouse B cells disrupts pre-mRNA splicing, alters cell development, and induces a state of cellular senescence. Combination with Atm deletion leads to the overcoming of cellular senescence and the development of CLL-like disease in elderly mice. These CLL-like cells show genome instability and dysregulation of multiple CLL-associated cellular processes, including deregulated B cell receptor signaling, which we also identified in human CLL cases. Notably, human CLLs harboring SF3B1 mutations exhibit altered response to BTK inhibition. Our murine model of CLL thus provides insights into human CLL disease mechanisms and treatment.
Identifiants
pubmed: 30712845
pii: S1535-6108(18)30585-3
doi: 10.1016/j.ccell.2018.12.013
pmc: PMC6372356
mid: NIHMS1007282
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
Phosphoproteins
0
Piperidines
0
Protein Kinase Inhibitors
0
Pyrazoles
0
Pyrimidines
0
RNA Splicing Factors
0
Receptors, Antigen, B-Cell
0
SF3B1 protein, human
0
Sf3b1 protein, mouse
0
ibrutinib
1X70OSD4VX
Agammaglobulinaemia Tyrosine Kinase
EC 2.7.10.2
Btk protein, mouse
EC 2.7.10.2
ATM protein, human
EC 2.7.11.1
Ataxia Telangiectasia Mutated Proteins
EC 2.7.11.1
Atm protein, mouse
EC 2.7.11.1
Adenine
JAC85A2161
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
283-296.e5Subventions
Organisme : NCI NIH HHS
ID : P01 CA203655
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA180861
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA240910
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL103532
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA216273
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA HL002346
Pays : United States
Organisme : NCI NIH HHS
ID : UG1 CA233338
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA006516
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA063113
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA206963
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM122524
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA206978
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA081534
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK087992
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA155010
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL116452
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA173023
Pays : United States
Informations de copyright
Copyright © 2018 Elsevier Inc. All rights reserved.
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