@article{060f8800a7e34a8a8a15ea5b47388a52,
title = "A Murine Model of Chronic Lymphocytic Leukemia Based on B Cell-Restricted Expression of Sf3b1 Mutation and Atm Deletion",
abstract = "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.",
keywords = "ATM, BCR signaling, CLL, SF3B1, murine model",
author = "Shanye Yin and Gambe, {Rutendo G.} and Jing Sun and Martinez, {Aina Zurita} and Cartun, {Zachary J.} and Regis, {Fara Faye D.} and Youzhong Wan and Jean Fan and Brooks, {Angela N.} and Herman, {Sarah E.M.} and Hacken, {Elisa ten} and Amaro Taylor-Weiner and Rassenti, {Laura Z.} and Ghia, {Emanuela M.} and Kipps, {Thomas J.} and Obeng, {Esther A.} and Cibulskis, {Carrie L.} and Donna Neuberg and Campagna, {Dean R.} and Fleming, {Mark D.} and Ebert, {Benjamin L.} and Adrian Wiestner and Ignaty Leshchiner and DeCaprio, {James A.} and Gad Getz and Robin Reed and Carrasco, {Ruben D.} and Wu, {Catherine J.} and Lili Wang",
note = "Funding Information: The authors thank Drs. Markus M{\H u}schen and Hassan Jumaa for their critical insights, and Ms. Sarah Hergert for excellent technical support. This work was in part supported by NCI 1R01 CA21673-01 (L.W. and C.J.W.), NCI 1R01 CA155010-01A1 (C.J.W.), NCI 1U10 CA180861-01 (C.J.W.), NHLBI 1R01 HL103532-01 (C.J.W.), NHLBI 1R01 HL116452-01 (C.J.W.), the Lymphoma Research Foundation (C.J.W.), a Leukemia Lymphoma Translational Research Program Award (C.J.W.); NIH R01 DK087992 (M.D.F.); NIH P01 CA81534 (T.J.K.), NIH Cancer Center Core Grant 5P30 CA006516 (D.N.); NIH R35 GM122524 (R.R.); NHLBI ZIA HL002346-13 (A.W.); US Public Health Service grants R01 CA63113 (J.A.D.), R01 CA173023 (J.A.D.), P01 CA203655 (J.A.D.); the Leukemia and Lymphoma Society fellowship (E.T.H.) and National Science Foundation Graduate Research Fellowship DGE1144152 (J.F.).C.J.W. is a co-founder of Neon therapeutics. C.J.W., D.N., and G.G. receive research funding from Pharmacyclics. B.L.E. has been a consultant for H3 Biomedicine and received research funding from Celgene. G.G. receives research funds from IBM. G.G. is an inventor on patent applications related to MuTect, ABSOLUTE, and other bioinformatics methods. J.A.D. has received honoraria for participation in advisory board from Merck. J.A.D. has received research funding from Constellation Pharmaceuticals. J.S. is a current employee of Moderna Therapeutics. All other authors declare no competing interests. Funding Information: C.J.W. is a co-founder of Neon therapeutics. C.J.W., D.N., and G.G. receive research funding from Pharmacyclics . B.L.E. has been a consultant for H3 Biomedicine and received research funding from Celgene . G.G. receives research funds from IBM . G.G. is an inventor on patent applications related to MuTect, ABSOLUTE, and other bioinformatics methods. J.A.D. has received honoraria for participation in advisory board from Merck . J.A.D. has received research funding from Constellation Pharmaceuticals . J.S. is a current employee of Moderna Therapeutics. All other authors declare no competing interests. Funding Information: The authors thank Drs. Markus M{\H u}schen and Hassan Jumaa for their critical insights, and Ms. Sarah Hergert for excellent technical support. This work was in part supported by NCI 1R01 CA21673-01 (L.W. and C.J.W.), NCI 1R01 CA155010-01A1 (C.J.W.), NCI 1U10 CA180861-01 (C.J.W.), NHLBI 1R01 HL103532-01 (C.J.W.), NHLBI 1R01 HL116452-01 (C.J.W.), the Lymphoma Research Foundation (C.J.W.), a Leukemia Lymphoma Translational Research Program Award (C.J.W.); NIH R01 DK087992 (M.D.F.); NIH P01 CA81534 (T.J.K.), NIH Cancer Center Core Grant 5P30 CA006516 (D.N.); NIH R35 GM122524 (R.R.); NHLBI ZIA HL002346-13 (A.W.); US Public Health Service grants R01 CA63113 (J.A.D.), R01 CA173023 (J.A.D.), P01 CA203655 (J.A.D.); the Leukemia and Lymphoma Society fellowship (E.T.H.) and National Science Foundation Graduate Research Fellowship DGE1144152 (J.F.). Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2019",
month = feb,
day = "11",
doi = "10.1016/j.ccell.2018.12.013",
language = "English (US)",
volume = "35",
pages = "283--296.e5",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "2",
}
