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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Bibliographic Details
Published in:British journal of haematology Vol. 205; no. 5; pp. 1804 - 1809
Main Authors: 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
Format: Journal Article
Language:English
Published: England Blackwell Publishing Ltd 01.11.2024
Subjects:
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
Online Access:Get full text
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Summary: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.
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ISSN:0007-1048
1365-2141
1365-2141
DOI:10.1111/bjh.19671