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PLCG2 C2 domain mutations co-occur with BTK and PLCG2 resistance mutations in chronic lymphocytic leukemia undergoing ibrutinib treatment

Leukemia volume 31, pages 1645–1647 (2017)Cite this article

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The Bruton agammaglobulinemia tyrosine kinase (BTK) amplifies B-cell receptor signaling through activation of phospholipase C gamma 2 (PLCG2). Clinical resistance in chronic lymphocytic leukemia (CLL) to the Bruton tyrosine kinase (BTK) inhibitor ibrutinib is highly associated with emergence of the BTK C481S mutation that prevents covalent binding of ibrutinib.1 Emergence of the BTK C481S-mutated CLL, beginning 2-3 years after therapy initiation, has been shown to correlate with disease progression and poor outcome but not large cell/Richter's transformation.2, 3, 4 In two recent studies, including one from our group, the detection of BTK C481 mutations, at low levels, preceded the development of overt resistance by 9–15 months.5, 6

Previous studies have also indicated a role for PLCG2 activating mutations in ibrutinib resistance in CLL including R665W and S707F localizing to the SH2 domain, L845F/V in the SH3 domain and D993X in the TIM-like barrel.7, 8 The SH2 and SH3 domain mutations likely alter the association of PLCG2 with linker proteins or influence SYK, LYN and BTK phosphorylation events but the resistance mechanisms, if any, underlying other sequence alterations are not known. We assess here how PLCG2 sequence variants (both germline and somatic) interact with each other and with BTK C481 mutations in a consecutive series of ibrutinib-treated CLL and delineate an additional PLCG2 hotspot for resistance-associated mutations.

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Acknowledgements

We thank all of the members of Polaris clinical laboratory and the Lozanski laboratory for assistance with these studies.

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Authors and Affiliations

  1. Department of Pathology, The Ohio State University and James Cancer Hospital, Columbus, OH, USA

    D Jones, W Zhao, J Coleman & G Lozanski

  2. Division of Hematology, Department of Internal Medicine, The Ohio State University and James Cancer Hospital, Columbus, OH, USA

    J A Woyach, J C Byrd & A J Johnson

  3. James Polaris Molecular Laboratory, The Ohio State University and James Cancer Hospital, Columbus, OH, USA

    S Caruthers & H Tu

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  1. D Jones
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  6. J Coleman
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  8. A J Johnson
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  9. G Lozanski
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Correspondence to D Jones.

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Competing interests

DJ, HT, JCB, GL, JAW and AJJ declare a conflict interest in intellectual property related to the diagnostics methods described in this manuscript. The remaining authors declare no conflict of interest.

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Jones, D., Woyach, J., Zhao, W. et al. PLCG2 C2 domain mutations co-occur with BTK and PLCG2 resistance mutations in chronic lymphocytic leukemia undergoing ibrutinib treatment. Leukemia 31, 1645–1647 (2017). https://doi.org/10.1038/leu.2017.110

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