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. 2024 Nov;205(5):1804-1809.
doi: 10.1111/bjh.19671. Epub 2024 Aug 26.

CREBBP histone acetyltransferase domain mutations predict response to mTOR inhibition in relapsed/refractory follicular lymphoma

Emil Arjun Kumar  1 , Koorosh Korfi  2 , Findlay Bewicke-Copley  1   2 , Karina Close  1 , James Heward  1 , Thomas Witzig  3 , Michael Leukam  4 , Stephen Ansell  3 , Jessica Scott  4 , Andrew Clear  2 , Alejo Efeyan  5 , Michael Green  6   7 , Reiner Siebert  8 , Barrie Peck  9 , Maria Calaminici  2 , Jun Wang  1 , Sonali Smith  4 , Anne Novak  3 , Jude Fitzgibbon  1 , Jessica Okosun  2
Affiliations

CREBBP histone acetyltransferase domain mutations predict response to mTOR inhibition in relapsed/refractory follicular lymphoma

Emil Arjun Kumar et al. Br J Haematol. 2024 Nov.

Abstract

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.

Keywords: CREBBP; follicular lymphoma; genetics; mTOR inhibition; mutation analysis.

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References

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