A Murine Model of Chronic Lymphocytic Leukemia Based on B Cell-Restricted Expression of Sf3b1 Mutation and Atm Deletion.

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.

• Publication year

  2019

• Venue

  Cancer Cell

• Publication date

  2019-02-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/j.ccell.2018.12.013PMID 30712845PMCID PMC6372356
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Pan-cancer analysis identifies mutations in SUGP1 that recapitulate mutant SF3B1 splicing dysregulation

  2020cited by this paper
• CRISPR/Cas9-generated models uncover therapeutic vulnerabilities of del(11q) CLL cells to dual BCR and PARP inhibition

  2020cited by this paper
• Clonal dynamics in chronic lymphocytic leukemia.

  2019cited by this paper
• Targeting B cell receptor signalling in cancer: preclinical and clinical advances

  2018cited by this paper
• Autoimmunity checkpoints as therapeutic targets in B cell malignancies

  2018influential reference
• Full-length transcript characterization of SF3B1 mutation in chronic lymphocytic leukemia reveals downregulation of retained introns

  2018cited by this paper
• Chronic lymphocytic leukaemia

  2017cited by this paper
• Chemical screening identifies ATM as a target for alleviating senescence.

  2017cited by this paper
• The evolutionary landscape of chronic lymphocytic leukemia treated with ibrutinib targeted therapy

  2017cited by this paper
• NFAT2 is a critical regulator of the anergic phenotype in chronic lymphocytic leukaemia

  2017influential reference
• Choosing frontline chemoimmunotherapy for CLL.

  2016cited by this paper
• Physiologic Expression of Sf3b1(K700E) Causes Impaired Erythropoiesis, Aberrant Splicing, and Sensitivity to Therapeutic Spliceosome Modulation.

  2016cited by this paper
• The Ensembl Variant Effect Predictor

  2016cited by this paper
• Cancer-associated SF3B1 mutations affect alternative splicing by promoting alternative branchpoint usage

  2016cited by this paper
• Transcriptomic Characterization of SF3B1 Mutation Reveals Its Pleiotropic Effects in Chronic Lymphocytic Leukemia.

  2016influential reference
• ATM couples replication stress and metabolic reprogramming during cellular senescence.

  2015cited by this paper
• Cancer-Associated SF3B1 Hotspot Mutations Induce Cryptic 3' Splice Site Selection through Use of a Different Branch Point.

  2015cited by this paper
• Chronic lymphocytic leukaemia

  2015cited by this paper
• Non-coding recurrent mutations in chronic lymphocytic leukaemia

  2015cited by this paper
• Mutations driving CLL and their evolution in progression and relapse

  2015influential reference
• Clinical impact of clonal and subclonal TP53, SF3B1, BIRC3, NOTCH1, and ATM mutations in chronic lymphocytic leukemia.

  2015cited by this paper
• Ibrutinib-induced lymphocytosis in patients with chronic lymphocytic leukemia: correlative analyses from a phase II study

  2014cited by this paper
• Age-related clonal hematopoiesis associated with adverse outcomes.

  2014cited by this paper
• Locally disordered methylation forms the basis of intratumor methylome variation in chronic lymphocytic leukemia.

  2014cited by this paper
• Age-related cancer mutations associated with clonal hematopoietic expansion

  2014cited by this paper
• The impact of SF3B1 mutations in CLL on the DNA-damage response

  2014cited by this paper
• Transcriptome characterization by RNA sequencing identifies a major molecular and clinical subdivision in chronic lymphocytic leukemia

  2014cited by this paper
• Early death in acute promyelocytic leukemia (APL) in French centers: a multicenter study in 399 patients

  2014cited by this paper
• Prolonged lymphocytosis during ibrutinib therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to therapy.

  2014cited by this paper
• Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples

  2013cited by this paper
• Immunological Genome Project and systems immunology.

  2013cited by this paper
• Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia.

  2013cited by this paper
• A positive/negative ion–switching, targeted mass spectrometry–based metabolomics platform for bodily fluids, cells, and fresh and fixed tissue

  2012cited by this paper
• Phospho-specific flow cytometry identifies aberrant signaling in indolent B-cell lymphoma

  2012influential reference
• Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling

  2012cited by this paper
• SF3B1 and other novel cancer genes in chronic lymphocytic leukemia.

  2011cited by this paper
• Conservation of an RNA regulatory map between Drosophila and mammals.

  2011cited by this paper
• Genome-Wide Association between Branch Point Properties and Alternative Splicing

  2010cited by this paper
• The genomic complexity of primary human prostate cancer

  2010cited by this paper
• The DLEU2/miR-15a/16-1 cluster controls B cell proliferation and its deletion leads to chronic lymphocytic leukemia.

  2010cited by this paper
• Molecular underpinning of B‐cell anergy

  2010influential reference
• Chronic lymphocytic leukaemia.

  2008cited by this paper
• Comparative Studies of Early Liver Dysfunction in Senescence-accelerated Mouse Using Mitochondrial Proteomics Approaches*S

  2008cited by this paper
• Complementary functions of ATM and H2AX in development and suppression of genomic instability

  2008cited by this paper
• Constitutive activation of distinct BCR-signaling pathways in a subset of CLL patients: a molecular signature of anergy.

  2008influential reference
• Cellular senescence: when bad things happen to good cells

  2007cited by this paper
• Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication

  2006cited by this paper
• Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints

  2006cited by this paper
• Unmutated and mutated chronic lymphocytic leukemias derive from self-reactive B cell precursors despite expressing different antibody reactivity.

  2005influential reference
• Genomic aberrations and survival in chronic lymphocytic leukemia.

  2000influential reference
• An alternatively spliced form of CD79b gene may account for altered B-cell receptor expression in B-chronic lymphocytic leukemia.

  1999cited by this paper

• Phase Ib study of PRT543, an oral protein arginine methyltransferase 5 (PRMT5) inhibitor, in patients with advanced splicing factor-mutant myeloid malignancies

  2025cites this paper
• SF3B1K700E mutation in human embryonic stem cells causes aberrant expression of immune-related genes

  2025cites this paper
• SF3B1 mutation accelerates the development of CLL via activation of the mTOR pathway

  2025influential citation
• A question of TiME: how microenvironmental interactions shape response to immunotherapy in CLL and Richter Transformation

  2025cites this paper
• ATM aberrations in chronic lymphocytic leukemia: del(11q) rather than ATM mutations is an adverse-prognostic biomarker

  2025cites this paper
• Identification of UBA7 expression downregulation in myelodysplastic neoplasm with SF3B1 mutations

  2025cites this paper
• Advancing the therapeutic effectiveness of paclitaxel in chronic lymphocytic leukemia through the simultaneous inhibition of NOTCH1 and SF3B1

  2025cites this paper
• MGA deletion leads to Richter’s transformation by modulating mitochondrial OXPHOS

  2024cites this paper
• Biological relevance of alternative splicing in hematologic malignancies

  2024cites this paper
• Mouse models of CLL: In vivo modeling of disease initiation, progression, and transformation to Richter transformation.

  2024cites this paper
• DNA damage response defects in hematologic malignancies: mechanistic insights and therapeutic strategies.

  2024cites this paper
• Leveraging genomics, transcriptomics and epigenomics to understand chemoimmunotherapy resistance in chronic lymphocytic leukemia

  2024cites this paper
• A novel multiscale framework for delineating cancer evolution from subclonal compositions.

  2024cites this paper
• The molecular map of CLL and Richter's syndrome.

  2024cites this paper
• Single-cell Rapid Capture Hybridization sequencing (scRaCH-seq) to reliably detect isoform usage and coding mutations in targeted genes at a single-cell level

  2024cites this paper
• Insights into genetic aberrations and signalling pathway interactions in chronic lymphocytic leukemia: from pathogenesis to treatment strategies

  2024cites this paper
• Recent Advances in the Molecular Biology of Chronic Lymphocytic Leukemia: How to Define Prognosis and Guide Treatment

  2024cites this paper
• Cancer-associated SF3B1-K700E mutation controls immune responses by regulating Treg function via aberrant Anapc13 splicing

  2024cites this paper
• The non-canonical BAF chromatin remodeling complex is a novel target of spliceosome dysregulation in SF3B1-mutated chronic lymphocytic leukemia

  2024cites this paper
• Engineering Oncogenic Hotspot Mutations on SF3B1 via CRISPR-Directed PRECIS Mutagenesis

  2024cites this paper
• Downregulation of UBA1 expression in myelodysplastic neoplasm

  2024cites this paper
• MGA deletion leads to Richter’s transformation via modulation of mitochondrial OXPHOS

  2023cites this paper
• AI-assisted proofreading of RNA splicing

  2023cites this paper
• Variations of intronic branchpoint motif: identification and functional implications in splicing and disease

  2023cites this paper
• Mutant SF3B1 promotes malignancy in PDAC

  2023cites this paper
• SF3B1 mutation–mediated sensitization to H3B-8800 splicing inhibitor in chronic lymphocytic leukemia

  2023cites this paper
• SF3B1 mutation and ATM deletion codrive leukemogenesis via centromeric R-loop dysregulation

  2023influential citation
• SF3B1 Mutations Are Associated with Resistance to Non-Genotoxic MDM2 Inhibition in Chronic Lymphocytic Leukemia

  2023cites this paper
• Inhibition of splicing factors SF3A3 and SRSF5 contributes to As3+/Se4+ combination-mediated proliferation suppression and apoptosis induction in acute promyelocytic leukemia cells.

  2023cites this paper
• METTL3-Mediated m6A Modification Controls Splicing Factor Abundance and Contributes to Aggressive CLL.

  2023cites this paper
• SF3B1 mutations in myelodysplastic syndromes: A potential therapeutic target for modulating the entire disease process

  2023cites this paper
• Regulation of Pre-mRNA Splicing: Indispensable Role of Post-Translational Modifications of Splicing Factors

  2023cites this paper
• RNA splicing factors in normal hematopoiesis and hematologic malignancies: novel therapeutic targets and strategies.

  2023cites this paper
• U2AF1 mutation connects DNA damage to the alternative splicing of RAD51 in lung adenocarcinomas

  2022cites this paper
• circRAB3IP modulates cell proliferation by reorganizing gene expression and mRNA processing in a paracrine manner

  2022cites this paper
• Subclonal heterogeneity sheds light on the transformation trajectory in IGLV3-21R110 chronic lymphocytic leukemia

  2022cites this paper
• The immune microenvironment shapes transcriptional and genetic heterogeneity in chronic lymphocytic leukemia

  2022cites this paper
• Chemokine Receptor 1 and its associated immune pathway are downregulated in SF3B1MT blood and non-blood cancers

  2022cites this paper
• ATM germline variants in a young adult with chronic lymphocytic leukemia: 8 years of genomic evolution

  2022cites this paper
• Mutant SF3B1 promotes PDAC malignancy through TGF-β resistance

  2022cites this paper
• The role of SF3B1 and NOTCH1 in the pathogenesis of leukemia

  2022influential citation
• Induction of chronic lymphocytic leukemia-like disease in STYK1/NOK transgenic mice.

  2022cites this paper
• The role of NPM1 alternative splicing in patients with chronic lymphocytic leukemia

  2022cites this paper
• Structural Insights into Branch Site Proofreading by Human Spliceosome

  2022cites this paper
• In vivo modeling of CLL transformation to Richter's syndrome reveals convergent evolutionary paths and therapeutic vulnerabilities.

  2022cites this paper
• Loss-of-function lesions impact B-cell development and fitness but are insufficient to drive CLL in mouse models

  2022cites this paper
• Physiopathologie de la leucémie lymphoïde chronique

  2021cites this paper
• Splicing modulators: on the way from nature to clinic

  2021cites this paper
• Biological significance of monoallelic and biallelic BIRC3 loss in del(11q) chronic lymphocytic leukemia progression

  2021cites this paper
• Splicing factor mutations in hematologic malignancies.

  2021cites this paper
• Advantages and disadvantages of mouse models of chronic lymphocytic leukemia in drug discovery

  2021cites this paper
• Single-cell sequencing technology in tumor research.

  2021cites this paper
• A hotspot mutation in transcription factor IKZF3 drives B cell neoplasia via transcriptional dysregulation.

  2021influential citation
• Dissecting the role of TP53 alterations in del(11q) chronic lymphocytic leukemia

  2021cites this paper
• The Effect of SF3B1 Mutation on the DNA Damage Response and Nonsense-Mediated mRNA Decay in Cancer

  2021cites this paper
• University of Birmingham Clonal evolution of high-risk chronic lymphocytic leukemia

  2021cites this paper
• Understanding CLL biology through mouse models of human genetics.

  2021cites this paper
• Activation of Notch and Myc Signaling via B-cell–Restricted Depletion of Dnmt3a Generates a Consistent Murine Model of Chronic Lymphocytic Leukemia

  2021cites this paper
• Two oppositely-charged sf3b1 mutations cause defective development, impaired immune response, and aberrant selection of intronic branch sites in Drosophila

  2021cites this paper
• Clonal Evolution of High-Risk Chronic Lymphocytic Leukemia: A Contemporary Perspective

  2021cites this paper
• Recent advance in nanomaterials for cancer immunotherapy

  2021cites this paper
• The Determinants of B Cell Receptor Signaling as Prototype Molecular Biomarkers of Leukemia

  2021cites this paper
• The Correlation Between Novel Survival-related Alternative Splicing Signature and Prognostic Prediction and Immune Microenvironment in Clear Cell Renal Cell Carcinoma

  2021cites this paper
• Mutant SF3B1 promotes AKT and NF-kB driven mammary tumorigenesis.

  2020cites this paper
• Meta-Analysis Reveals Significant Sex Differences in Chronic Lymphocytic Leukemia Progression in the Eµ-TCL1 Transgenic Mouse Model

  2020cites this paper
• Prognostic and Predictive Molecular Biomarkers in Chronic Lymphocytic Leukemia.

  2020cites this paper
• RNA Splicing and Cancer.

  2020cites this paper
• Mouse Models in the Study of Mature B-Cell Malignancies.

  2020cites this paper
• P2X7 promotes the progression of MLL-AF9-induced acute myeloid leukemia by upregulation of Pbx3

  2020cites this paper
• Splicing dysregulation in cancer: from mechanistic understanding to a new class of therapeutic targets

  2020cites this paper
• Genomic and Epigenomic Alterations in Chronic Lymphocytic Leukemia.

  2020cites this paper
• Pan-cancer analysis identifies mutations in SUGP1 that recapitulate mutant SF3B1 splicing dysregulation

  2020cites this paper
• CRISPR/Cas9-generated models uncover therapeutic vulnerabilities of del(11q) CLL cells to dual BCR and PARP inhibition

  2020cites this paper
• E3 Ligase, UBR5, HECT domain mutations in lymphoma control maturation of B cells.

  2020cites this paper
• The role of alternative splicing in cancer: From oncogenesis to drug resistance.

  2020cites this paper
• Relative strength of 5’ splice-site strength defines functions of SRSF2 and SRSF6 in alternative splicing of Bcl-x pre-mRNA

  2020cites this paper
• A reduced panel of eight genes (ATM, SF3B1, NOTCH1, BIRC3, XPO1, MYD88, TNFAIP3, and TP53) as an estimator of the tumor mutational burden in chronic lymphocytic leukemia

  2020cites this paper
• Somatic SF3B1 mutations in myelodysplastic syndrome with ring sideroblasts and chronic lymphocytic leukaemia

  2019cites this paper
• Somatic SF 3 B 1 mutations in myelodysplastic syndrome with ring sideroblasts and chronic lymphocytic leukaemia

  2019cites this paper
• High expression of PRKDC promotes breast cancer cell growth via p38 MAPK signaling and is associated with poor survival

  2019cites this paper
• Clonal dynamics in chronic lymphocytic leukemia.

  2019cites this paper
• SF3B1 cancer-related mutations cause vulnerability to further perturbations in the U2 snRNP complex in C. elegans

  2019cites this paper
• CRISPR editing of sftb-1/SF3B1 in C. elegans allows the identification of synthetic interactions with cancer-related mutations and the chemical inhibition of splicing

  2019cites this paper
• PRKDC is a prognostic marker for poor survival in gastric cancer patients and regulates DNA damage response.

  2019cites this paper
• Modeling of SF3B1 cancer-related missense mutations in C. elegans uncovers targets for synthetic lethal interactions

  2019cites this paper
• Targeted therapies in CLL. New drugs against CLL recurrent mutations

  2019cites this paper
• CRISPR editing of sftb-1/SF3B1 in Caenorhabditis elegans allows the identification of synthetic interactions with cancer-related mutations and the chemical inhibition of splicing

  2019cites this paper
• Clonal dynamics in chronic lymphocytic leukemia.

  2019cites this paper
• Full-length transcript characterization of SF3B1 mutation in chronic lymphocytic leukemia reveals downregulation of retained introns

  2018cites this paper
• Transformation of Indolent Lymphomas and Chronic Lymphocytic Leukemia (CLL) New Insights into the Transformation of Indolent Lymphomas and CLL From in Vivo Models

  year unknowncites this paper