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

Shanye Yin; Rutendo G. Gambe; Jing Sun; Aina Zurita Martinez; Zachary J. Cartun; Fara Faye D. Regis; Youzhong Wan; Jean Fan; Angela N. Brooks; Sarah E.M. Herman; Elisa ten Hacken; Amaro Taylor-Weiner; Laura Z. Rassenti; Emanuela M. Ghia; Thomas J. Kipps; Esther A. Obeng; Carrie L. Cibulskis; Donna Neuberg; Dean R. Campagna; Mark D. Fleming; Benjamin L. Ebert; Adrian Wiestner; Ignaty Leshchiner; James A. DeCaprio; Gad Getz; Robin Reed; Ruben D. Carrasco; Catherine J. Wu; Lili Wang

doi:10.1016/j.ccell.2018.12.013

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

Shanye Yin, Rutendo G. Gambe, Jing Sun, Aina Zurita Martinez, Zachary J. Cartun, Fara Faye D. Regis, Youzhong Wan, Jean Fan, Angela N. Brooks, Sarah E.M. Herman, Elisa ten Hacken, Amaro Taylor-Weiner, Laura Z. Rassenti, Emanuela M. Ghia, Thomas J. Kipps, Esther A. Obeng, Carrie L. Cibulskis, Donna Neuberg, Dean R. Campagna, Mark D. FlemingBenjamin L. Ebert, Adrian Wiestner, Ignaty Leshchiner, James A. DeCaprio, Gad Getz, Robin Reed, Ruben D. Carrasco, Catherine J. Wu, Lili Wang

Research output: Contribution to journal › Article › peer-review

58 Scopus citations

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.

Original language	English (US)
Pages (from-to)	283-296.e5
Journal	Cancer Cell
Volume	35
Issue number	2
DOIs	https://doi.org/10.1016/j.ccell.2018.12.013
State	Published - Feb 11 2019
Externally published	Yes

Keywords

ATM
BCR signaling
CLL
SF3B1
murine model

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccell.2018.12.013

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Yin, S., Gambe, R. G., Sun, J., Martinez, A. Z., Cartun, Z. J., Regis, F. F. D., Wan, Y., Fan, J., Brooks, A. N., Herman, S. E. M., Hacken, E. T., Taylor-Weiner, A., Rassenti, L. Z., Ghia, E. M., Kipps, T. J., Obeng, E. A., Cibulskis, C. L., Neuberg, D., Campagna, D. R., ... Wang, L. (2019). A Murine Model of Chronic Lymphocytic Leukemia Based on B Cell-Restricted Expression of Sf3b1 Mutation and Atm Deletion. Cancer Cell, 35(2), 283-296.e5. https://doi.org/10.1016/j.ccell.2018.12.013

Yin, S, Gambe, RG, Sun, J, Martinez, AZ, Cartun, ZJ, Regis, FFD, Wan, Y, Fan, J, Brooks, AN, Herman, SEM, Hacken, ET, Taylor-Weiner, A, Rassenti, LZ, Ghia, EM, Kipps, TJ, Obeng, EA, Cibulskis, CL, Neuberg, D, Campagna, DR, Fleming, MD, Ebert, BL, Wiestner, A, Leshchiner, I, DeCaprio, JA, Getz, G, Reed, R, Carrasco, RD, Wu, CJ & Wang, L 2019, 'A Murine Model of Chronic Lymphocytic Leukemia Based on B Cell-Restricted Expression of Sf3b1 Mutation and Atm Deletion', Cancer Cell, vol. 35, no. 2, pp. 283-296.e5. https://doi.org/10.1016/j.ccell.2018.12.013

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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",

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AU - Yin, Shanye

AU - Gambe, Rutendo G.

AU - Sun, Jing

AU - Martinez, Aina Zurita

AU - Cartun, Zachary J.

AU - Regis, Fara Faye D.

AU - Wan, Youzhong

AU - Fan, Jean

AU - Brooks, Angela N.

AU - Herman, Sarah E.M.

AU - Hacken, Elisa ten

AU - Taylor-Weiner, Amaro

AU - Rassenti, Laura Z.

AU - Ghia, Emanuela M.

AU - Kipps, Thomas J.

AU - Obeng, Esther A.

AU - Cibulskis, Carrie L.

AU - Neuberg, Donna

AU - Campagna, Dean R.

AU - Fleming, Mark D.

AU - Ebert, Benjamin L.

AU - Wiestner, Adrian

AU - Leshchiner, Ignaty

AU - DeCaprio, James A.

AU - Getz, Gad

AU - Reed, Robin

AU - Carrasco, Ruben D.

AU - Wu, Catherine J.

AU - Wang, Lili

PY - 2019/2/11

Y1 - 2019/2/11

N2 - 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.

AB - 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.

KW - ATM

KW - BCR signaling

KW - CLL

KW - SF3B1

KW - murine model

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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