Abstract
A recurrent activating mutation in phospholipase C, gamma 1 (PLCG1) is found in 19% of CTCL samples.
Major finding: A recurrent activating mutation in phospholipase C, gamma 1 (PLCG1) is found in 19% of CTCL samples.
Mechanism: CTCL-associated PLCG1 mutants activate calcineurin signaling and induce NFAT nuclear translocation.
Impact: Inhibitors of PLC or calcineurin signaling may be effective in PLCG1-mutant CTCLs.
Cutaneous T-cell lymphomas (CTCL) are a heterogenous group of indolent non-Hodgkin lymphomas distinguished by expansion of malignant T cells in the skin. The genetic etiology and subsequent molecular changes that drive CTCL growth are poorly understood, and there are no effective targeted therapies for the most aggressive CTCL subtypes. Given that increased T-cell receptor (TCR) signaling has been linked to CTCL development, Vaqué and colleagues sequenced 524 TCR signaling-associated genes in 11 mycosis fungoides and Sézary syndrome samples and matched normal tissue. Other than TP53, the only recurrently mutated gene was phospholipase C, gamma1 (PLCG1), which was mutated in three samples, two of which had the same S345F missense mutation. Screening of an additional cohort identified the PLCG1S345F mutation in a total of 10 of 53 (19%) samples. PLCG1 phosphodiesterase activity leads to the activation of calcineurin signaling, which induces nuclear localization of the transcription factor nuclear factor of activated T cells (NFAT) and upregulation of NFAT target genes. Consistent with in silico modeling that predicted increased phosphodiesterase activity of the S345F mutant, PLCG1-mutant samples showed increased NFAT nuclear localization, and ectopic expression of PLCG1S345F activated a luciferase reporter system driven by an NFAT response element. Furthermore, NFAT activation in cells expressing the S345F mutant could be reversed with a calcineurin or PLC inhibitor, providing further evidence that the S345F mutation leads to gain of PLCG1 activity. Of note, calcineurin or PLC inhibition reduced NFAT activity, suppressed proliferation, and increased cell death in CTCL cell lines that did not harbor a PLCG1 mutation, suggesting that PLCG1-driven activation of NFAT may be a common feature of CTCLs. These results collectively reveal that PLCG1 is genetically altered in a significant portion of CTCLs and suggest that targeting PLC or calcineurin may be an effective therapeutic strategy in CTCL.
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