CREBBP 组蛋白乙酰转移酶结构域突变可预测复发/难治性滤泡性淋巴瘤对 mTOR 抑制的反应。
CREBBP histone acetyltransferase domain mutations predict response to mTOR inhibition in relapsed/refractory follicular lymphoma.
发表日期：2024 Aug 26
作者：
Emil Arjun Kumar, Koorosh Korfi, Findlay Bewicke-Copley, Karina Close, James Heward, Thomas Witzig, Michael Leukam, Stephen Ansell, Jessica Scott, Andrew Clear, Alejo Efeyan, Michael Green, Reiner Siebert, Barrie Peck, Maria Calaminici, Jun Wang, Sonali Smith, Anne Novak, Jude Fitzgibbon, Jessica Okosun
来源：
BRITISH JOURNAL OF HAEMATOLOGY
摘要：
尽管滤泡性淋巴瘤 (FL) 具有临床和分子异质性，但在常规临床实践中仍然缺乏生物标志物导向的治疗方法，但 EZH2 突变型 FL 中的 EZH2 抑制剂他泽美司他是一个明显的例外。在这里，我们通过对临床试验中接受 mTORi 依维莫司或替西罗莫司治疗的 21 名复发/难治性 FL 患者的活检进行靶向突变分析，研究了基因突变状态是否可以预测 FL 对临床 mTOR 抑制剂 (mTORi) 的反应。我们观察到 mTORi 应答者中 CREBBP 催化组蛋白乙酰转移酶 (HAT) 结构域内的突变富集，并描述了包含这些突变的 FL 的独特转录特征和共存突变；强化了人们对 CREBBPHAT 突变作为关键生物决定因素的认识，及其作为佛罗里达州治疗生物标志物的前景。© 2024 作者。英国血液学杂志由英国血液学会和约翰·威利出版
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.© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.