The role of B cell antigen receptors in mantle cell lymphoma

Fichtner, Michael; Dreyling, Martin; Binder, Mascha; Trepel, Martin

doi:10.1186/s13045-017-0533-9

Cited by 23 publications

(23 citation statements)

References 120 publications

(141 reference statements)

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“…MCL cell lines and primary tumors show active BCR signaling, which leads to activation of BTK and downstream NF-kB or the PI3K-AKT pathway that drive cell proliferation and survival. [2][3][4][5][6] BCR-targeting agents have been tested in preclinical and clinical settings and demonstrated success in controlling MCL. 7,8 Remarkably, the BTK inhibitor, ibrutinib (ibr), has achieved an overall response rate of 68% and median progression-free survival of 13.9 months in relapsed and refractory patients with MCL, 9 and the drug has been approved for the treatment of MCL in this particular setting.…”

Section: Introductionmentioning

confidence: 99%

Activation of MYC, a bona fide client of HSP90, contributes to intrinsic ibrutinib resistance in mantle cell lymphoma

Lee

Zhang

et al. 2018

Blood Advances

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The BTK inhibitor ibrutinib has demonstrated a remarkable therapeutic effect in mantle cell lymphoma (MCL). However, approximately one-third of patients do not respond to the drug initially. To identify the mechanisms underlying primary ibrutinib resistance in MCL, we analyzed the transcriptome changes in ibrutinib-sensitive and ibrutinib-resistant cell lines on ibrutinib treatment. We found that MYC gene signature was suppressed by ibrutinib in sensitive but not resistant cell lines. We demonstrated that MYC gene was structurally abnormal and MYC protein was overexpressed in MCL cells. Further, MYC knockdown with RNA interference inhibited cell growth in ibrutinib-sensitive as well as ibrutinib-resistant cells. We explored the possibility of inhibiting MYC through HSP90 inhibition. The chaperon protein is overexpressed in both cell lines and primary MCL cells from the patients. We demonstrated that MYC is a bona fide client of HSP90 in the context of MCL by both immunoprecipitation and chemical precipitation. Furthermore, inhibition of HSP90 using PU-H71 induced apoptosis and caused cell cycle arrest. PU-H71 also demonstrates strong and relatively specific inhibition of the MYC transcriptional program compared with other oncogenic pathways. In a MCL patient-derived xenograft model, the HSP90 inhibitor retards tumor growth and prolongs survival. Last, we showed that PU-H71 induced apoptosis and downregulated MYC protein in MCL cells derived from patients who were clinically resistant to ibrutinib. In conclusion, MYC activity underlies intrinsic resistance to ibrutinib in MCL. As a client protein of HSP90, MYC can be inhibited via PU-H71 to overcome primary ibrutinib resistance.

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Section: Introductionmentioning

confidence: 99%

Activation of MYC, a bona fide client of HSP90, contributes to intrinsic ibrutinib resistance in mantle cell lymphoma

Lee

Zhang

et al. 2018

Blood Advances

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“…CD79b is a component of the B cell receptor (BCR) complex [100]. It is a promising therapeutic target because of its restricted expression on mature B cells and B cell malignancies [101].…”

Section: Polatuzumab Vedotin (Polivy® Dcdts4501a)mentioning

confidence: 99%

Antibody-drug conjugates in clinical trials for lymphoid malignancies and multiple myeloma

Liu

2019

J Hematol Oncol

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Antibody-drug conjugates (ADC) represent a distinct family of chemoimmunotherapy agents. ADCs are composed of monoclonal antibodies conjugated to cytotoxic payloads via specialized chemical linkers. ADCs therefore combine the immune therapy with targeted chemotherapy. Due to the distinct biomarkers associated with lymphocytes and plasma cells, ADCs have emerged as a promising treatment option for lymphoid malignancies and multiple myeloma. Several ADCs have been approved for clinical applications: brentuximab vedotin, inotuzumab ozogamicin, moxetumomab pasudotox, and polatuzumab vedotin. More novel ADCs are under clinical development. In this article, we summarized the general principles for ADC design, and updated novel ADCs under various stages of clinical trials for lymphoid malignancies and multiple myeloma.

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“…105,106 Immunogenetic studies have shown a biased usage of certain IGHV genes (IGHV3-21, IGHV4-34, IGHV1-8, and IGHV3-23), suggesting antigen-driven selection, whereas completely unmutated IGHV genes are detected in~30% of the cases, which have a worse prognosis than cases with IGH somatic hypermutations. 107,108 The genomic landscape of MCL is heterogeneous, and comprises mutations in genes involved in DNA damage response (ATM and TP53) and Notch signalling (NOTCH1 and NOTCH2), and in genes affecting RNA metabolism and splicing (EWSR1, DAZAP1, and HNRNPH1). Mutations in TP53, SMARCA4, CELSR3, CCND1 and KMT2D have been found to negatively affect the response to venetoclax-based therapies.…”

Section: Molecular Geneticsmentioning

confidence: 99%

Recent advances in upper gastrointestinal lymphomas: molecular updates and diagnostic implications

2020

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Approximately one‐third of extranodal non‐Hodgkin lymphomas involve the gastrointestinal (GI) tract, with the vast majority being diagnosed in the stomach, duodenum, or proximal small intestine. A few entities, especially diffuse large B‐cell lymphoma and extranodal marginal zone lymphoma of mucosa‐associated lymphoid tissue, represent the majority of cases. In addition, there are diseases specific to or characteristic of the GI tract, and any type of systemic lymphoma can present in or disseminate to these organs. The recent advances in the genetic and molecular characterisation of lymphoid neoplasms have translated into notable changes in the classification of primary GI T‐cell neoplasms and the recommended diagnostic approach to aggressive B‐cell tumours. In many instances, diagnoses rely on morphology and immunophenotype, but there is an increasing need to incorporate molecular genetic markers. Moreover, it is also important to take into consideration the endoscopic and clinical presentations. This review gives an update on the most recent developments in the pathology and molecular pathology of upper GI lymphoproliferative diseases.

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The role of B cell antigen receptors in mantle cell lymphoma

Cited by 23 publications

References 120 publications

Activation of MYC, a bona fide client of HSP90, contributes to intrinsic ibrutinib resistance in mantle cell lymphoma

Activation of MYC, a bona fide client of HSP90, contributes to intrinsic ibrutinib resistance in mantle cell lymphoma

Antibody-drug conjugates in clinical trials for lymphoid malignancies and multiple myeloma

Recent advances in upper gastrointestinal lymphomas: molecular updates and diagnostic implications

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