BTK kinase activity is dispensable for the survival of diffuse large B-cell lymphoma

• DOI: 10.1016/j.jbc.2022.102555
• Publication Date: 2022-09-29T15:30:32Z
• Authors: Hongwei Yuan; Yutong Zhu; Yalong Cheng; Junjie Hou; Fengjiao Jin; Menglin Li; Wei Jia; Zhenzhen Cheng; Haimei Xing; Mike Liu; Ting Han
• Keywords: B-Lymphocytes; 0303 health sciences; 03 medical and health sciences; Agammaglobulinaemia Tyrosine Kinase; Humans; Receptors, Antigen, B-Cell; Lymphoma, Large B-Cell, Diffuse; Protein Kinase Inhibitors; Research Article; Signal Transduction

Inhibitors targeting Bruton's tyrosine kinase (BTK) have revolutionized the treatment for various B-cell malignancies but are limited by acquired resistance after prolonged as a result of mutations in BTK. Here, combination structural modeling, vitro assays, and deep phospho-tyrosine proteomics, we demonstrated that four clinically observed BTK mutations-C481F, C481Y, C481R, L528W-inactivated activity both diffused large lymphoma (DLBCL) cells. Paradoxically, found DLBCL cells harboring kinase-inactive exhibited intact B cell receptor (BCR) signaling, unperturbed transcription, optimal cellular growth. Moreover, determined with remained addicted to BCR signaling were thus sensitive targeted degradation proteolysis-targeting chimera. By performing parallel genome-wide CRISPR-Cas9 screening WT or BTK, discovered displayed increased dependence on Toll-like 9 (TLR9) their growth and/or survival. Our study demonstrates is not essential oncogenic suggests BTK's noncatalytic function sufficient sustain survival DLBCL.