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

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

SUBMITTER: Yuan H

PROVIDER: S-EPMC9636578 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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

Yuan Hongwei H Zhu Yutong Y Cheng Yalong Y Hou Junjie J Jin Fengjiao F Li Menglin M Jia Wei W Cheng Zhenzhen Z Xing Haimei H Liu Mike M Han Ting T

The Journal of biological chemistry 20220929 11

Inhibitors targeting Bruton's tyrosine kinase (BTK) have revolutionized the treatment for various B-cell malignancies but are limited by acquired resistance after prolonged treatment as a result of mutations in BTK. Here, by a combination of structural modeling, in vitro assays, and deep phospho-tyrosine proteomics, we demonstrated that four clinically observed BTK mutations-C481F, C481Y, C481R, and L528W-inactivated BTK kinase activity both in vitro and in diffused large B-cell lymphoma (DLBCL) ...[more]

PMID: 36183831

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Project description:BackgroundDiffuse large B-cell lymphoma (DLBCL) constitutes 30% of all non-Hodgkin's lymphomas. It can present as a nodal disease or as an extra nodal disease. Based on the site of origin, extra nodal DLBCL (EN-DLBCL) may have a distinct clinical outcome. Apart from the site of origin, factors including demographics, stage, and presence of any other primary malignancy also affect the outcome. The purpose of our study was to characterize prognostically distinct groups based on the site of presentation of EN-DLBCL.MethodsWe used 18 registries in Surveillance, Epidemiology, and End Results database to identify the patients with EN-DLBCL for 2000 - 2015 with last follow-up till December 31, 2018. A total of 30,290 EN-DLBCL patients were selected and categorized based on 13 broad sites grouping. Demographic variables were summarized. We did overall survival analysis with univariate and multivariate Cox-proportional hazard modeling. Short-term survival trend was calculated as well.ResultsThe percentage of EN-DLBCL of all DLBCLs is 34.48%. EN-DLBCL was comparatively seen more in males (54.94%) and non-Hispanic whites (71.52%). In terms of clinical characteristics, patients with EN-DLBCL were mostly diagnosed at age ≥ 60 years (66.11%), early stage (69.33%), and presentation as first primary cancer (81.89%). A higher risk of mortality was seen in non-Hispanic black (hazard ratio (HR) 1.36), with late age of onset (HR 2.69), late stage at presentation (HR 1.42), and with history of other malignancy (HR 1.29). Compared to the intestinal tract, the risk of overall mortality was higher in individuals with involvement of nervous system (HR 1.85), pancreas and hepatobiliary system (HR 1.22), and respiratory system (HR 1.18) and the best outcomes were seen in heart and mediastinal site (HR 0.58) of DLBCL.ConclusionBased upon our population-based study, we conclude that primary site of presentation of EN-DLBCL is an important prognostic factor with significant difference in survival based on histological and epidemiological characteristics.

Project description:BackgroundPatients infected with HIV have a significantly increased risk of developing non-Hodgkin lymphomas despite the widespread use of HAART. To investigate mTOR pathway activity in acquired immunodeficiency syndrome (AIDS) related diffuse large B-cell lymphoma AR-DLBCL, we used immunohistochemistry to examine the presence of the phosphorylated 70 ribosomal S6 protein-kinase (p70S6K), an extensively studied effector of mTOR Complex 1 (mTORC1) and the phosphorylated phosphatase and tensin homolog (pPTEN), a negative regulator of mTORC1 pathway.Materials and methodsWe evaluated tissue samples from 126 patients with AR-DLBCL. Among them, 98 samples were from tissue microarrays (TMAs) supplied by the Aids and Cancer Specimen Resource (ACSR), the remaining 28 samples were from cases diagnosed and treated at the University of California, San Diego (UCSD). The presence of p70S6K was evaluated with two antibodies directed against the combined epitopes Ser235/236 and Ser240/244, respectively; and additional monoclonal anti-bodies were used to identify pPTEN and phosphorylated proline-rich Akt substrate of 40kDa (pPRAS40). The degree of intensity and percentage of cells positive for p70S6K and pPTEN were assessed in all the samples. In addition, a subgroup of 28 patients from UCSD was studied to assess the presence of pPRAS40, an insulin-regulated activator of the mTORC1. The expression of each of these markers was correlated with clinical and histopathologic features.ResultsThe majority of the patients evaluated were males (88%); only two cases (1.6%) were older than 65 years of age. We found high levels of both p70S6K-paired epitopes studied, 48% positivity against Ser235/236 (44% in ACSR and 64% in UCSD group), and 86% positivity against Ser240/244 (82% in ACSR and 100% in UCSD group). We observed more positive cells and stronger intensity with epitope Ser240/244 in comparison to Ser235/236 (p<0.0001). The degree of intensity and percentage of cells positive for pPTEN was positively correlated with p70S6K levels (p = 0.016 for 235/236 and p = 0.007 for 240/244). High levels of pPRAS40 were observed in the majority of the cases evaluated (64.3%), but no correlation was found with either pPTEN (p = 0.9) or p70S6K (p = 0.9) levels.ConclusionAR-DLBCL frequently contain p70S6K, a main downstream effector of the mTOR pathway. The presence of p70S6K is positively correlated with pPTEN, an inactive form of PTEN, which makes mTORC1 activated. The presence of p70S6K was independent of HIV viral load or CD4 (+) counts. These results suggest that the mTOR pathway is active in the majority of AR-DLBCL, and p70S6K, particularly the Ser240/244 epitope immunohistochemistry is an excellent surrogate biomarker, which could be used to identify cases expected to be responsive to mTOR inhibitors.

Project description:Objectives/hypothesisThis study utilizes a large population national database to comprehensively analyze prognosticators and overall survival (OS) outcomes of varying treatment modalities in a large cohort of sinonasal diffuse large B-cell lymphoma (SN-DLBCL) patients.Study designRetrospective database study.MethodsThe National Cancer Database was queried for all SN-DLBCL cases diagnosed from 2004 to 2015. Kaplan-Meier log-rank test determined differences in OS based on clinical covariates. Cox proportional-hazards analysis was used to determine clinical and sociodemographic covariates predictive of mortality.ResultsA total of 2,073 SN-DLBCL patients were included, consisting of 48% female with a mean age of 66.0 ± 16.2 years. Overall, 82% of patients were Caucasian, 74% had early-stage disease, and 49% had primary tumors in the paranasal sinuses. Early-stage patients were more likely to receive multi-agent chemoradiotherapy compared to multi-agent chemotherapy alone (P < .001). Multivariable Cox proportional-hazards analysis revealed chemoradiotherapy to confer significantly greater OS improvements than chemotherapy alone (hazard ratio [HR]: 0.61; P < .001). However, subset analysis of late-stage patients demonstrated no significant differences in OS between these treatment modalities (P = .245). On multivariable analysis of chemotherapy patients treated post-2012, immunotherapy (HR = 0.51; P = .024) demonstrated significant OS benefits. However, subset analysis showed no significant advantage in OS with administering immunotherapy for late-stage patients (P = .326). Lastly, for all patients treated post-2012, those receiving immunotherapy had significantly improved OS compared to those not receiving immunotherapy (P < .001).ConclusionsTreatment protocol selection differs between early- and late-stage SN-DLBCL patients. Early-stage patients receiving chemotherapy may benefit from immunotherapy as part of their treatment paradigm.Level of evidence3 Laryngoscope, 131:E2727-E2735, 2021.

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

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

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