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

Summary 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 mutatio...

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Vydané v:	British journal of haematology Ročník 205; číslo 5; s. 1804 - 1809
Hlavní autori:	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
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	England Blackwell Publishing Ltd 01.11.2024
Predmet:	Aged Biomarkers Biopsy Clinical trials CREB-Binding Protein - genetics CREBBP Everolimus - therapeutic use Female follicular lymphoma genetics Histone acetyltransferase Humans Lymphoma Lymphoma, Follicular - drug therapy Lymphoma, Follicular - genetics Male Middle Aged mTOR inhibition MTOR Inhibitors - pharmacology MTOR Inhibitors - therapeutic use Mutation mutation analysis Point mutation Protein Domains Recurrence Sirolimus - analogs & derivatives TOR protein TOR Serine-Threonine Kinases - antagonists & inhibitors mTOR inhibition CREBBP genetics follicular lymphoma mutation analysis
ISSN:	0007-1048, 1365-2141, 1365-2141
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Shrnutí:	Summary 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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	0007-1048 1365-2141 1365-2141
DOI:	10.1111/bjh.19671