Hyperactive PLCG1 induces cell-autonomous and bystander T cell activation and drug resistance
Phospholipase C gamma 1 (PLCG1) has been identified as the most frequently mutated gene in adult T-cell leukemia/lymphoma, suggesting a critical function of PLCG1 in driving T cell activation. However, it remains unclear how these mutations regulate T cell physiology and pathology. Here, we investigate three common leukemia/lymphoma-associated mutations (R48W, S345F, and D1165H). We discover that these mutations induce hyperactive T cell signaling and cause pro-survival phenotypes. PLCG1 mutants enhance LAT condensation, calcium influx, and ERK activation. They also promote T cell proliferation, upregulate cell adhesion molecules, induce cell aggregation, and confer resistance to Vorinostat, an FDA-approved drug for cutaneous T-cell lymphoma. The resistance depends on ERK signaling and can be reversed with an ERK inhibitor. Interestingly, PLCG1 mutants also induce bystander drug resistance in nearby cells expressing wild-type PLCG1. Mechanistically, alpha smooth muscle actin, which is specifically induced by PLCG1 mutants, directly binds PLCG1 to promote its activation. These results demonstrate that hyperactive PLCG1 promotes T cell survival and drug resistance by inducing non-canonical signaling.
Authors
- Yiwei Xiong (ORCID: https://orcid.org/0000-0002-6205-4691)
- John Sondek (ORCID: https://orcid.org/0000-0002-1127-8310)
- Yasunori Kogure (ORCID: https://orcid.org/0000-0003-1158-5131)
- Keisuke Kataoka (ORCID: https://orcid.org/0000-0002-8263-9902)
- K. Satoh (ORCID: https://orcid.org/0000-0001-8516-292X)
- Nicole Hajicek (ORCID: https://orcid.org/0000-0001-7457-4830)
- Xiaolei Su (ORCID: https://orcid.org/0000-0001-8696-7922)
- Seishi Ogawa (ORCID: https://orcid.org/0000-0002-7778-5374)
- Longhui Zeng (ORCID: https://orcid.org/0009-0008-2761-5570)
- Xinyan Zhang (ORCID: https://orcid.org/0000-0001-6269-3138)
Institutions
- University of North Carolina at Chapel Hill (US)
- Keio University (JP)
- Kyoto University (JP)
- Yale Cancer Center (US)
- Yale University (US)
- Kindai University (JP)
Publication Details
- Journal
- EMBO Reports
- Published
- 2025-08-12
- DOI
- https://doi.org/10.1038/s44319-025-00546-x
- Citations
- 3
- Primary Topic
- T-cell and Retrovirus Studies
- Type
- article
- Field-Weighted Citation Impact
- 2.39
Funders
- American Cancer Society
- Cancer Research Institute
- Rally Foundation
- Yale University
- Division of Cancer Prevention, National Cancer Institute
- Yale Cancer Center
- Pershing Square Sohn Cancer Research Alliance
- Human Frontier Science Program
- University of Tokyo
- Daiichi Sankyo Foundation of Life Science
- National Institutes of Health
- Yale SPORE in Lung Cancer
- Japan Society for the Promotion of Science
- National Cancer Institute
- National Institute of General Medical Sciences
- Yale Liver Center
- Daiichi Sankyo Europe