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

Wenjun Wu, Weige Wang, Carrie A. Franzen, Hui Guo, Jimmy Lee, Yan Li, Madina Sukhanova, Dong Sheng, Girish Venkataraman, Mei Ming, Pin Lu, Anhui Gao, Chunmei Xia, Jia Li, Liang Leo Zhang, Vivian Changying Jiang, Michael L. Wang, Jorge Andrade, Xiaoyan Zhou, Y. Lynn Wang

Research output: Contribution to journalArticlepeer-review

Abstract

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 ibrutinibinduced 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 ;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.

Original languageEnglish (US)
Pages (from-to)185-197
Number of pages13
JournalBlood Advances
Volume5
Issue number1
DOIs
StatePublished - Jan 12 2021

ASJC Scopus subject areas

  • Hematology

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