Inhibition of B-cell receptor signaling disrupts cell adhesion in mantle cell lymphoma via RAC2

doi:10.1182/bloodadvances.2020001665

	Inhibition of B-cell receptor signaling disrupts cell adhesion in mantle cell lymphoma via RAC2
	Wu, Wenjun 1; Wang, Weige 2,3,9; Franzen, Carrie A.3; Guo, Hui 4; Lee, Jimmy 3; Li, Yan 8; Sukhanova, Madina 5; Sheng, Dong 2,9; Venkataraman, Girish 6; Ming, Mei 3
刊名	BLOOD ADVANCES
	2021-01-12
卷号	5 期号:1 页码:185-197
ISSN号	2473-9529
DOI	10.1182/bloodadvances.2020001665
通讯作者	Wang, Y. Lynn(yuelynn.wang@fccc.edu)
英文摘要	Inhibition of the B-cell receptor (BCR) signaling pathway is highly effective in B-cell neoplasia through Bruton tyrosine kinase inhibition by ibrutinib. Ibrutinib also disrupts cell adhesion between a tumor and its microenvironment. However, it is largely unknown how BCR signaling is linked to cell adhesion. We observed that intrinsic sensitivities of mantle cell lymphoma (MCL) cell lines to ibrutinib correlated well with their cell adhesion phenotype. RNA-sequencing revealed that BCR and cell adhesion signatures were simultaneously downregulated by ibrutinib in the ibrutinib-sensitive, but not ibrutinib-resistant, cells. Among the differentially expressed genes, RAC2, part of the BCR signature and a known regulator of cell adhesion, was downregulated at both the RNA and protein levels by ibrutinib only in sensitive cells. RAC2 physically associated with B-cell linker protein (BLNK), a BCR adaptor molecule, uniquely in sensitive cells. RAC2 reduction using RNA interference and CRISPR impaired cell adhesion, whereas RAC2 overexpression reversed ibrutinib-induced cell adhesion impairment. In a xenograft mouse model, mice treated with ibrutinib exhibited slower tumor growth, with reduced RAC2 expression in tissue. Finally, RAC2 was expressed in similar to 65% of human primary MCL tumors, and RAC2 suppression by ibrutinib resulted in cell adhesion impairment. These findings, made with cell lines, a xenograft model, and human primary lymphoma tumors, uncover a novel link between BCR signaling and cell adhesion. This study highlights the importance of RAC2 and cell adhesion in MCL pathogenesis and drug development.
资助项目	China Scholar Council ; Leukemia & Lymphoma Society[TRP6364-13] ; National Natural Science Foundation of China[81470353] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020208]
WOS关键词	TYROSINE KINASE INHIBITOR ; CHRONIC LYMPHOCYTIC-LEUKEMIA ; IBRUTINIB RESISTANCE ; ANTITUMOR-ACTIVITY ; T-CELL ; BTK ; EXPRESSION ; SYK ; MUTATION ; COMBINATION
WOS研究方向	Hematology
语种	英语
出版者	AMER SOC HEMATOLOGY
WOS记录号	WOS:000607932700020
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/290417]
专题	中国科学院上海药物研究所
通讯作者	Wang, Y. Lynn
作者单位	1.Fox Chase Canc Ctr, Blood Cell Dev & Funct Program, Philadelphia, PA 19111 USA 2.Fudan Univ, Dept Oncol, Shanghai Med Sch, Shanghai, Peoples R China 3.Univ Chicago, Dept Pathol, Lymphoma Translat Pathol, 5841 S Maryland Ave, Chicago, IL 60637 USA 4.Univ Texas MD Anderson Canc Ctr, Dept Lymphoma & Myeloma, Houston, TX 77030 USA 5.Northwestern Univ, Dept Pathol, Chicago, IL 60611 USA 6.Univ Chicago, Dept Pathol, Sect Hematopathol, 5841 S Maryland Ave, Chicago, IL 60637 USA 7.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China 8.Univ Chicago, Ctr Res Informat, Chicago, IL USA 9.Fudan Univ, Dept Pathol, Shanghai Canc Ctr, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Wu, Wenjun,Wang, Weige,Franzen, Carrie A.,et al. Inhibition of B-cell receptor signaling disrupts cell adhesion in mantle cell lymphoma via RAC2[J]. BLOOD ADVANCES,2021,5(1):185-197.
APA	Wu, Wenjun.,Wang, Weige.,Franzen, Carrie A..,Guo, Hui.,Lee, Jimmy.,...&Wang, Y. Lynn.(2021).Inhibition of B-cell receptor signaling disrupts cell adhesion in mantle cell lymphoma via RAC2.BLOOD ADVANCES,5(1),185-197.
MLA	Wu, Wenjun,et al."Inhibition of B-cell receptor signaling disrupts cell adhesion in mantle cell lymphoma via RAC2".BLOOD ADVANCES 5.1(2021):185-197.