干旱区生态环境知识资源中心(Arid): CARD11 gain of function upregulates BCL2A1 expression and promotes resistance to targeted therapies combination in B-cell lymphoma

Arid

DOI	10.1182/blood.2023020211
	CARD11 gain of function upregulates BCL2A1 expression and promotes resistance to targeted therapies combination in B-cell lymphoma
	Decombis, Salome; Bellanger, Celine; Le Bris, Yannick; Madiot, Candice; Jardine, Jane; Santos, Juliana Carvalho; Boulet, Delphine; Dousset, Christelle; Menard, Audrey; Kervoelen, Charlotte; Douillard, Elise; Moreau, Philippe; Minvielle, Stephane; Moreau-Aubry, Agnes; Tessoulin, Benoit; Roue, Gael; Bidere, Nicolas; Le Gouill, Steven; Pellat-Deceunynck, Catherine; Chiron, David
通讯作者	Chiron, D
来源期刊	BLOOD
ISSN	0006-4971
EISSN	1528-0020
出版年	2023
卷号	142 期号:18 页码:1543-1555
英文摘要	A strategy combining targeted therapies is effective in B-cell lymphomas (BCL), such as mantle cell lymphoma (MCL), but acquired resistances remain a recurrent issue. In this study, we performed integrative longitudinal genomic and single-cell RNA-sequencing analyses of patients with MCL who were treated with targeted therapies against CD20, BCL2, and Bruton tyrosine kinase (OAsIs trial). We revealed the emergence of subclones with a selective advantage against OAsIs combination in vivo and showed that resistant cells were characterized by B-cell receptor (BCR)-independent overexpression of NF-.B1 target genes, especially owing to CARD11 mutations. Functional studies demonstrated that CARD11 gain of function not only resulted in BCR independence but also directly increased the transcription of the antiapoptotic BCL2A1, leading to resistance against venetoclax and OAsIs combination. Based on the transcriptional profile of OAsIs-resistant subclones, we designed a 16-gene resistance signature that was also predictive for patients with MCL who were treated with conventional chemotherapy, underlying a common escape mechanism. Among druggable strategies to inhibit CARD11-dependent NF-kappa B1 transduction, we evaluated the selective inhibition of its essential partner MALT1. We demonstrated that MALT1 protease inhibition led to a reduction in the expression of genes involved in OAsIs resistance, including BCL2A1. Consequently, MALT1 inhibition induced synergistic cell death in combination with BCL2 inhibition, irrespective of CARD11 mutational status, both in vitro and in vivo. Taken together, our study identified mechanisms of resistance to targeted therapies and provided a novel strategy to overcome resistance in aggressive BCL. The OAsIs trial was registered at www.clinicaltrials.gov #NCT02558816.
类型	Article
语种	英语
开放获取类型	Green Submitted
收录类别	SCI-E
WOS记录号	WOS:001113959200001
WOS关键词	BRUTON TYROSINE KINASE ; ABT-199 RESISTANCE ; MANTLE ; IBRUTINIB ; VENETOCLAX ; ACTIVATION ; MUTATION ; PATIENT ; MALT1 ; BTK
WOS类目	Hematology
WOS研究方向	Hematology
资源类型	期刊论文
条目标识符	http://119.78.100.177/qdio/handle/2XILL650/395580
推荐引用方式 GB/T 7714	Decombis, Salome,Bellanger, Celine,Le Bris, Yannick,et al. CARD11 gain of function upregulates BCL2A1 expression and promotes resistance to targeted therapies combination in B-cell lymphoma[J],2023,142(18):1543-1555.
APA	Decombis, Salome.,Bellanger, Celine.,Le Bris, Yannick.,Madiot, Candice.,Jardine, Jane.,...&Chiron, David.(2023).CARD11 gain of function upregulates BCL2A1 expression and promotes resistance to targeted therapies combination in B-cell lymphoma.BLOOD,142(18),1543-1555.
MLA	Decombis, Salome,et al."CARD11 gain of function upregulates BCL2A1 expression and promotes resistance to targeted therapies combination in B-cell lymphoma".BLOOD 142.18(2023):1543-1555.