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ResearchIn-Press PreviewHematologyOncology Open Access | 10.1172/jci.insight.184280

SF3B1 mutation accelerates the development of CLL via activation of the mTOR pathway

Bo Zhang,1 Prajish Iyer,1 Meiling Jin,1 Elisa ten Hacken,3 Zachary Cartun,4 Kevyn L. Hart,1 Mike Fernandez,1 Kristen Stevenson,5 Laura Rassenti,6 Emanuela M. Ghia,6 Thomas J. Kipps,6 Donna Neuberg,5 Ruben Carrasco,3 Wing Chan,7 Joo Y. Song,7 Yu Hu,8 Catherine Wu,3 and Lili Wang1

1Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, China

2Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, United States of America

3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Medical Oncology, Dana-Farber Cancder Institute, Boston, United States of America

5Department of Data Science, Dana-Farber Cancer Institute, Boston, United States of America

6Moores Cancer Center, University of California San Diego Health, La Jolla, United States of America

7Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, United States of America

8Tongji Medical College, Huazhong University of Science & Technology, Huazhong University of Science and Technology, Wuhan, China

Find articles by Zhang, B. in: PubMed | Google Scholar

1Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, China

2Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, United States of America

3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Medical Oncology, Dana-Farber Cancder Institute, Boston, United States of America

5Department of Data Science, Dana-Farber Cancer Institute, Boston, United States of America

6Moores Cancer Center, University of California San Diego Health, La Jolla, United States of America

7Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, United States of America

8Tongji Medical College, Huazhong University of Science & Technology, Huazhong University of Science and Technology, Wuhan, China

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1Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, China

2Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, United States of America

3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Medical Oncology, Dana-Farber Cancder Institute, Boston, United States of America

5Department of Data Science, Dana-Farber Cancer Institute, Boston, United States of America

6Moores Cancer Center, University of California San Diego Health, La Jolla, United States of America

7Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, United States of America

8Tongji Medical College, Huazhong University of Science & Technology, Huazhong University of Science and Technology, Wuhan, China

Find articles by Jin, M. in: PubMed | Google Scholar

1Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, China

2Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, United States of America

3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Medical Oncology, Dana-Farber Cancder Institute, Boston, United States of America

5Department of Data Science, Dana-Farber Cancer Institute, Boston, United States of America

6Moores Cancer Center, University of California San Diego Health, La Jolla, United States of America

7Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, United States of America

8Tongji Medical College, Huazhong University of Science & Technology, Huazhong University of Science and Technology, Wuhan, China

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1Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, China

2Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, United States of America

3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Medical Oncology, Dana-Farber Cancder Institute, Boston, United States of America

5Department of Data Science, Dana-Farber Cancer Institute, Boston, United States of America

6Moores Cancer Center, University of California San Diego Health, La Jolla, United States of America

7Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, United States of America

8Tongji Medical College, Huazhong University of Science & Technology, Huazhong University of Science and Technology, Wuhan, China

Find articles by Cartun, Z. in: PubMed | Google Scholar

1Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, China

2Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, United States of America

3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Medical Oncology, Dana-Farber Cancder Institute, Boston, United States of America

5Department of Data Science, Dana-Farber Cancer Institute, Boston, United States of America

6Moores Cancer Center, University of California San Diego Health, La Jolla, United States of America

7Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, United States of America

8Tongji Medical College, Huazhong University of Science & Technology, Huazhong University of Science and Technology, Wuhan, China

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1Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, China

2Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, United States of America

3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Medical Oncology, Dana-Farber Cancder Institute, Boston, United States of America

5Department of Data Science, Dana-Farber Cancer Institute, Boston, United States of America

6Moores Cancer Center, University of California San Diego Health, La Jolla, United States of America

7Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, United States of America

8Tongji Medical College, Huazhong University of Science & Technology, Huazhong University of Science and Technology, Wuhan, China

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1Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, China

2Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, United States of America

3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Medical Oncology, Dana-Farber Cancder Institute, Boston, United States of America

5Department of Data Science, Dana-Farber Cancer Institute, Boston, United States of America

6Moores Cancer Center, University of California San Diego Health, La Jolla, United States of America

7Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, United States of America

8Tongji Medical College, Huazhong University of Science & Technology, Huazhong University of Science and Technology, Wuhan, China

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1Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, China

2Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, United States of America

3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Medical Oncology, Dana-Farber Cancder Institute, Boston, United States of America

5Department of Data Science, Dana-Farber Cancer Institute, Boston, United States of America

6Moores Cancer Center, University of California San Diego Health, La Jolla, United States of America

7Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, United States of America

8Tongji Medical College, Huazhong University of Science & Technology, Huazhong University of Science and Technology, Wuhan, China

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1Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, China

2Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, United States of America

3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Medical Oncology, Dana-Farber Cancder Institute, Boston, United States of America

5Department of Data Science, Dana-Farber Cancer Institute, Boston, United States of America

6Moores Cancer Center, University of California San Diego Health, La Jolla, United States of America

7Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, United States of America

8Tongji Medical College, Huazhong University of Science & Technology, Huazhong University of Science and Technology, Wuhan, China

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1Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, China

2Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, United States of America

3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Medical Oncology, Dana-Farber Cancder Institute, Boston, United States of America

5Department of Data Science, Dana-Farber Cancer Institute, Boston, United States of America

6Moores Cancer Center, University of California San Diego Health, La Jolla, United States of America

7Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, United States of America

8Tongji Medical College, Huazhong University of Science & Technology, Huazhong University of Science and Technology, Wuhan, China

Find articles by Kipps, T. in: PubMed | Google Scholar

1Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, China

2Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, United States of America

3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Medical Oncology, Dana-Farber Cancder Institute, Boston, United States of America

5Department of Data Science, Dana-Farber Cancer Institute, Boston, United States of America

6Moores Cancer Center, University of California San Diego Health, La Jolla, United States of America

7Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, United States of America

8Tongji Medical College, Huazhong University of Science & Technology, Huazhong University of Science and Technology, Wuhan, China

Find articles by Neuberg, D. in: PubMed | Google Scholar |

1Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, China

2Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, United States of America

3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Medical Oncology, Dana-Farber Cancder Institute, Boston, United States of America

5Department of Data Science, Dana-Farber Cancer Institute, Boston, United States of America

6Moores Cancer Center, University of California San Diego Health, La Jolla, United States of America

7Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, United States of America

8Tongji Medical College, Huazhong University of Science & Technology, Huazhong University of Science and Technology, Wuhan, China

Find articles by Carrasco, R. in: PubMed | Google Scholar

1Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, China

2Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, United States of America

3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Medical Oncology, Dana-Farber Cancder Institute, Boston, United States of America

5Department of Data Science, Dana-Farber Cancer Institute, Boston, United States of America

6Moores Cancer Center, University of California San Diego Health, La Jolla, United States of America

7Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, United States of America

8Tongji Medical College, Huazhong University of Science & Technology, Huazhong University of Science and Technology, Wuhan, China

Find articles by Chan, W. in: PubMed | Google Scholar

1Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, China

2Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, United States of America

3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Medical Oncology, Dana-Farber Cancder Institute, Boston, United States of America

5Department of Data Science, Dana-Farber Cancer Institute, Boston, United States of America

6Moores Cancer Center, University of California San Diego Health, La Jolla, United States of America

7Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, United States of America

8Tongji Medical College, Huazhong University of Science & Technology, Huazhong University of Science and Technology, Wuhan, China

Find articles by Song, J. in: PubMed | Google Scholar

1Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, China

2Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, United States of America

3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Medical Oncology, Dana-Farber Cancder Institute, Boston, United States of America

5Department of Data Science, Dana-Farber Cancer Institute, Boston, United States of America

6Moores Cancer Center, University of California San Diego Health, La Jolla, United States of America

7Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, United States of America

8Tongji Medical College, Huazhong University of Science & Technology, Huazhong University of Science and Technology, Wuhan, China

Find articles by Hu, Y. in: PubMed | Google Scholar

1Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, China

2Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, United States of America

3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Medical Oncology, Dana-Farber Cancder Institute, Boston, United States of America

5Department of Data Science, Dana-Farber Cancer Institute, Boston, United States of America

6Moores Cancer Center, University of California San Diego Health, La Jolla, United States of America

7Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, United States of America

8Tongji Medical College, Huazhong University of Science & Technology, Huazhong University of Science and Technology, Wuhan, China

Find articles by Wu, C. in: PubMed | Google Scholar

1Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, China

2Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, United States of America

3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

4Department of Medical Oncology, Dana-Farber Cancder Institute, Boston, United States of America

5Department of Data Science, Dana-Farber Cancer Institute, Boston, United States of America

6Moores Cancer Center, University of California San Diego Health, La Jolla, United States of America

7Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, United States of America

8Tongji Medical College, Huazhong University of Science & Technology, Huazhong University of Science and Technology, Wuhan, China

Find articles by Wang, L. in: PubMed | Google Scholar

Published July 22, 2025 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.184280.
Copyright © 2025, Zhang et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published July 22, 2025 - Version history
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Abstract

RNA splicing factor SF3B1 is one of the most recurrently mutated genes in chronic lymphocytic leukemia (CLL) and frequently co-occurs with chromosome 13q deletion (del(13q)). This combination is associated with poor prognosis in CLL, suggesting these lesions increase CLL aggressiveness. While del(13q) in murine B cells (Mdr mice), but not expression of Sf3b1-K700E, drives the initiation of CLL, we hypothesize that SF3B1 mutation accelerates CLL progression. In this study, we crossed mice with a B-cell-specific Sf3b1-K700E allele with Mdr mice to determine the impact of Sf3b1 mutation on CLL progression. We found that the co-occurrence of these two lesions in murine B cells caused acceleration of CLL. We showed that Sf3b1-K700E impacted alternative RNA splicing of Nfatc1 and activated mTOR signaling and the MYC pathway, contributing to CLL acceleration. Moreover, concurrent inhibition of RNA splicing and mTOR pathways led to cell death in vitro and in vivo in murine CLL cells with SF3B1 mutation and del(13q). Our results thus suggest that SF3B1 mutation contributes to the aggressiveness of CLL by activating the mTOR pathway through alternative splicing of Nfatc1, providing a rationale for targeting mTOR and RNA splicing in the subset of CLL patients with both SF3B1 mutations and del(13q).

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