British journal of haematology · 2024
CREBBP histone acetyltransferase domain mutations predict response to mTOR inhibition in relapsed/refractory follicular lymphoma.
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Kumar Emil Arjun, Korfi Koorosh, Bewicke-Copley Findlay, Close Karina, Heward James, Witzig Thomas, Leukam Michael, Ansell Stephen, Scott Jessica, Clear Andrew, Efeyan Alejo, Green Michael, Siebert Reiner, Peck Barrie, Calaminici Maria, Wang Jun, Smith Sonali, Novak Anne, Fitzgibbon Jude, Okosun Jessica
Аннотация
Despite the clinical and molecular heterogeneity of follicular lymphoma (FL), there remains a lack of biomarker-directed therapeutic approaches in routine clinical practice, with the notable exception of the EZH2 inhibitor tazemetostat in EZH2-mutant FL. Here we examined whether gene mutation status predicts response to clinical mTOR inhibitors (mTORi) in FL, by performing targeted mutational profiling of biopsies from 21 relapsed/refractory FL patients treated with mTORi everolimus or temsirolimus within clinical trials. We observed an enrichment of mutations within the catalytic histone acetyltransferase (HAT) domain of CREBBP in mTORi-responders, and describe distinct transcriptional characteristics and co-occurring mutations of FL harbouring these mutations; reinforcing the growing appreciation of CREBBPHAT mutation as a key biological determinant and its promise as a therapeutic biomarker in FL.