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

Hu, Yuan; Zhu, Yao; Cheng, Yalong; Hou, Junjie; Jin, Fengjiao; Li, Menglin; Jia, Wei; Cheng, Zhengxing; Xing, Haimei; Liu, Mike; Han, Ting

doi:10.1016/j.jbc.2022.102555

Cited by 15 publications

(20 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the knockout cells, we observed that re-addition of BTK induces CD69 only in the presence of stimulation, indicating that BTK activity still requires the endogenous regulatory signals when the protein is added using a lentivirus (Figure 2B). In keeping with previous reports, some CD69 expression is observed in the knockout cells when adding back a control virus, indicating that other signaling molecules or pathways contribute to the B-cell response in these cells (Yuan et al, 2022). Even in wild-type Ramos cells, some CD69 expression is observed without simulation or additional expression of a kinase (Figure 2A), presumably due to the low but detectable amount of phospo-PLCγ2 constitutively present in this line (Kim et al, 2004).…”

Section: Resultssupporting

confidence: 91%

“…Unlike many other B-cell lines, the Ramos line does not depend on BTK for cell growth (Yuan et al, 2022). Nevertheless, Ramos cells exhibit BTK-dependent calcium responses (Yuan et al, 2022) and correlated CD69 upregulation (Haselmayer et al, 2019). Jurkat T cells are a T-cell leukemia line derived from a human male (Weiss et al, 1984).…”

Section: Resultsmentioning

confidence: 99%

“…The role of BTK in some human B-cell lines, and the Ramos line in particular, is unusual. Mutations that disrupt BTK kinase activity fully support BTK-induced calcium flux in Ramos and TMD8 cells (Dhami et al, 2022; Yuan et al, 2022). These results are reminiscent of earlier studies that show that the K430R mutation in the kinase domain of BTK (which alters the interaction of the kinase with ATP and attenuates or abolishes kinase activity (Xu et al, 2000)) reconstitutes most of B-cell development in a Btk -knockout mouse (Middendorp et al, 2003).…”

Section: Resultsmentioning

confidence: 99%

“…That BTK may be playing different roles in different cell types has been highlighted by studies showing that in some cells, BTK is required for signaling but its kinase activity is not (Dhami et al, 2022; Wang et al, 2022; Yuan et al, 2022). In diffuse large B-cell lymphoma (DLBCL), inhibition of BTK kinase activity is an effective treatment, indicating that cancer progression requires kinase-active BTK.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Conditional Requirement for Dimerization of the Membrane-Binding Module of BTK

Eisen,

Ghaffari-Kashani,

Groves

et al. 2023

Preprint

View full text Add to dashboard Cite

Bruton’s tyrosine kinase (BTK) functions in many types of immune cells and is a major chemotherapeutic target. BTK is activated at the plasma membrane and can dimerize through its pleckstrin-homology and contiguous tec-homology domains (the PH–TH module). The features that support dimerization of the PH–TH module are unique to BTK among the Tec kinases and appeared relatively recently in evolutionary history. Previous studies suggest that dimerization enhances kinase activity by promotingtransautophosphorylation, but whether BTK dimerizes in cells via the PH–TH module, and whether this dimerization controls signaling, is unknown. To address this question, we developed a high-throughput mutagenesis assay for BTK function in B cells and T cells. We measured the fitness costs for thousands of point mutations in the PH–TH module and kinase domain, allowing us to assess whether dimerization of the PH–TH module and BTK kinase activity are necessary for function. In Ramos B cells we find that neither dimerization nor kinase activity is required for BTK signaling. Instead, in Ramos cells, BTK signaling is enhanced by mutations that increase membrane adsorption, even at the cost of reduced PH–TH dimerization. In contrast, in Jurkat T cells, we find that BTK signaling depends on PH–TH dimerization and also on kinase activity. These results provide a framework for understanding why PH–TH dimerization is a more recent evolutionary innovation that is not conserved across the Tec family.

show abstract

Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Conditional Requirement for Dimerization of the Membrane-Binding Module of BTK

Eisen,

Ghaffari-Kashani,

Groves

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…We recently identified that certain drug resistance mutations in BTK are associated with reduced autophosphorylation of BTK at Y223 (5) (29,30).…”

Section: Drug Resistance Mutations In Btk Have Distinct Enzymatic Act...mentioning

confidence: 99%

Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127

Montoya,

Bourcier,

Noviski

et al. 2024

Science

View full text Add to dashboard Cite

Increasing use of covalent and noncovalent inhibitors of Bruton’s tyrosine kinase (BTK) has elucidated a series of acquired drug-resistant BTK mutations in patients with B cell malignancies. Here we identify inhibitor resistance mutations in BTK with distinct enzymatic activities, including some that impair BTK enzymatic activity while imparting novel protein-protein interactions that sustain B cell receptor (BCR) signaling. Furthermore, we describe a clinical-stage BTK and IKZF1/3 degrader, NX-2127, that can bind and proteasomally degrade each mutant BTK proteoform, resulting in potent blockade of BCR signaling. Treatment of chronic lymphocytic leukemia with NX-2127 achieves >80% degradation of BTK in patients and demonstrates proof-of-concept therapeutic benefit. These data reveal an oncogenic scaffold function of mutant BTK that confers resistance across clinically approved BTK inhibitors but is overcome by BTK degradation in patients.

show abstract