Hypermorphic mutation of phospholipase C, γ2 acquired in ibrutinib-resistant CLL confers BTK independency upon B-cell receptor activation
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Key Points: Hypermorphic PLCγ2 is independent of BTK activation. SYK or LYN inhibition antagonizes mutant PLCγ2-mediated signaling events.
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In vitro, SYK and LYN were essential in the mutated hypermorphic PLCγ2 (R665W) signaling, a common relapse patient PLCγ2 mutation.
“It was also demonstrated in vitro SYK and LYN were essential in the mutated hypermorphic PLCγ2 (R665W) signaling, a common relapse patient PLCγ2 mutation, suggesting SYK and LYN as alternative targets in Ibrutinib resistance (132).”
From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [132]
The Introduction reports functional dependence of PLCγ2 R665W signaling on SYK and LYN, and the Results show that inhibitors of either kinase reduced signaling in vitro. The Results identify R665W in three patients who relapsed on ibrutinib, but do not establish that it is a common mutation among relapse patients. (LLM, conf=0.82)
Experimental — accuracy not yet measuredAbout 75% of mutations in PLCG2 previously implicated in various inflammatory diseases map to the autoinhibitory interface on the PLCγ2 model structure and can be considered pathogenic.
“A number of mutations in PLCG2 (about 75%), that have been previously implicated in various inflammatory diseases [92–102], actually map to the autoinhibitory interface on the PLCγ2 model structure and can be considered as pathogenic (Fig. 2c)”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [99]
The Results and Discussion (page not provided) place the disease-associated S707Y mutation in an autoinhibitory region of PLCγ2 and describe its hypermorphic effect. They do not report that about 75% of inflammatory-disease-associated PLCG2 mutations map to an autoinhibitory interface on a model structure, or classify that group as pathogenic. (LLM, conf=0.86)
Experimental — accuracy not yet measuredInhibitors of Syk and Lyn have been shown to oppose ibrutinib resistance mediated by PLCG2 mutations.
“Thus, inhibitors of Syk and Lyn have been shown to oppose ibrutinib resistance mediated by PLCG2 mutations (31).”
Btk-independent activation of the overexpressed R665W PLCγ2 mutant after B cell receptor engagement in Btk-deficient DT40 cells suggests Btk independency of this mutant.
“Very recent evidence showed Btk-independent activation of the overexpressed R665W PLC␥ 2 mutant after B cell receptor engagement in Btk-deficient DT40 cells, suggesting Btk independency of this mutant (31).”
When R665W was expressed in PLCγ2-deficient DT40 cells containing endogenous wild-type Btk, BCR-mediated PLCγ2 activation was resistant to ibrutinib but sensitive to pharmacologic inhibitors of Syk and Lyn.
“When the same mutant was expressed in PLC␥ 2 -deficient DT40 cells containing endogenous wild-type Btk, BCR-mediated PLC␥ 2 activation was resistant to ibrutinib, but sensitive to pharmacologic inhibitors of Syk and Lyn.”
BCR-mediated activation of PLCγ2 R665W was enhanced even in Btk-/- cells compared with the wild-type enzyme, suggesting that the mutant functionally bypasses Btk upon BCR activation.
“Subsequent experiments in reconstituted DT40 cells showed that BCR-mediated activation of PLC␥ 2 R665W was enhanced even in Btk Ϫ/Ϫ cells in comparison with the wild-type enzyme, suggesting that the mutant functionally bypasses Btk upon BCR activation (31).”
Studies have shown that mutant PLCG2 protein can be activated via kinases LYN and SYK and also suggest functional dependency of PLCG2 on LYN and SYK.
“Studies have shown that mutant PLCG2 protein can be activated via kinases LYN and SYK and also suggest functional dependency of PLCG2 on LYN and SYK (46).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [46]
PLCG2 GOF polymorphisms have been recently associated with other disorders, such as inflammatory bowel disease and resistance of chronic lymphocytic leukaemia cells to the BTK inhibitor ibrutinib.
“PLCG2 GOF polymorphisms have also been recently associated with other disorders, such as inflammatory bowel disease [114] and resistance of chronic lymphocytic leukaemia cells to the BTK inhibitor ibrutinib [99, 115]”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [99]
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“It was also demonstrated in vitro SYK and LYN were essential in the mutated hypermorphic PLCγ2 (R665W) signaling, a common relapse patient PLCγ2 mutation, suggesting SYK and LYN as alternative targets in Ibrutinib resistance (132).”
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Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy
Gruessner, C., Wiestner, A., & Sun, C. (2025) · Leukemia & Lymphoma · doi:10.1080/10428194.2025.2466101 · Cited by 6 · see citing works
“Studies have shown that mutant PlcG2 protein can be activated via kinases lYN and SYK and also suggest functional dependency of PlcG2 on lYN and SYK [45]. in this way, lYN and SYK, can contribute to activation of PlcG2 bypassing BtK.”
- Authors
- Liu, T.-M., Woyach, J. A., Zhong, Y., Lozanski, A., Lozanski, G., Dong, S., Strattan, E., Lehman, A., Zhang, X., Jones, J. A., Flynn, J., Andritsos, L. A., Maddocks, K., Jaglowski, S. M., Blum, K. A., Byrd, J. C., Dubovsky, J. A., & Johnson, A. J.
- Affiliations
- Department of Internal Medicine, Division of Hematology, and
- The Ohio State University Wexner Medical Center (US)
- The Ohio State University (US)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2015-07-02
- Volume
- 126
- Issue
- 1
- Pages
- 61-68
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC4492196
- OpenAlex
- W914588906
- Cited by
- 178
- References
- 7
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 20 · 2023: 13 · 2022: 17 · 2021: 22 · 2020: 21 · 2019: 13 · 2018: 10 · 2017: 24 · 2016: 17 · 2015: 4 · 2014: 1
- FWCI
- 10.27
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Blood (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (4p01ca081534-16)
- National Cancer Institute (P01CA095426, P50CA140158, R01CA183444, P01CA95426, K23CA178183, P30CA016058, R01CA177292, P01-CA-081534)
- Topics
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Keywords
- chronic lymphocytic leukemia, ibrutinib resistance, PLCγ2, B cell receptor signaling, Syk, Lyn kinase, BTK inhibitors
- MeSH terms
- Syk Kinase, Agammaglobulinaemia Tyrosine Kinase, Adenine, Animals, Antineoplastic Combined Chemotherapy Protocols, Cells, Cultured, Chickens, Humans, Piperidines, Protein-Tyrosine Kinases, Pyrazoles, Pyrimidines, Receptors, Antigen, B-Cell, Signal Transduction, Leukemia, Lymphocytic, Chronic, B-Cell, Drug Resistance, Neoplasm, src-Family Kinases, Mutation, Missense, Intracellular Signaling Peptides and Proteins, Phospholipase C gamma
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