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  1. Article ; Online: BCL2 inhibition: back to the future!

    Dyer, Martin J S / Walter, Harriet S

    Blood

    2024  Volume 143, Issue 18, Page(s) 1787–1788

    MeSH term(s) Humans ; Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Antineoplastic Agents/therapeutic use ; Antineoplastic Agents/pharmacology ; Animals ; Apoptosis/drug effects
    Chemical Substances Proto-Oncogene Proteins c-bcl-2 ; Antineoplastic Agents ; BCL2 protein, human
    Language English
    Publishing date 2024-05-02
    Publishing country United States
    Document type Journal Article
    ZDB-ID 80069-7
    ISSN 1528-0020 ; 0006-4971
    ISSN (online) 1528-0020
    ISSN 0006-4971
    DOI 10.1182/blood.2023023796
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

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  2. Article ; Online: Chronic lymphocytic leukaemia therapy: is less more?

    Walter, Harriet S / Dyer, Martin J S

    The Lancet. Haematology

    2022  Volume 9, Issue 3, Page(s) e169–e171

    MeSH term(s) Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy ; Pyrazoles ; Pyrimidines
    Chemical Substances Pyrazoles ; Pyrimidines
    Language English
    Publishing date 2022-03-03
    Publishing country England
    Document type Journal Article ; Comment
    ISSN 2352-3026
    ISSN (online) 2352-3026
    DOI 10.1016/S2352-3026(22)00044-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Impact of the clinically approved BTK inhibitors on the conformation of full-length BTK and analysis of the development of BTK resistance mutations in chronic lymphocytic leukemia.

    Joseph, Raji E / Wales, Thomas E / Jayne, Sandrine / Britton, Robert G / Fulton, D Bruce / Engen, John R / Dyer, Martin J S / Andreotti, Amy H

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Inhibition of Bruton's tyrosine kinase (BTK) has proven to be highly effective in the treatment of B-cell malignancies such as chronic lymphocytic leukemia (CLL), autoimmune disorders and multiple sclerosis. Since the approval of the first BTK inhibitor ( ...

    Abstract Inhibition of Bruton's tyrosine kinase (BTK) has proven to be highly effective in the treatment of B-cell malignancies such as chronic lymphocytic leukemia (CLL), autoimmune disorders and multiple sclerosis. Since the approval of the first BTK inhibitor (BTKi), Ibrutinib, several other inhibitors including Acalabrutinib, Zanubrutinib, Tirabrutinib and Pirtobrutinib have been clinically approved. All are covalent active site inhibitors, with the exception of the reversible active site inhibitor Pirtobrutinib. The large number of available inhibitors for the BTK target creates challenges in choosing the most appropriate BTKi for treatment. Side-by-side comparisons in CLL have shown that different inhibitors may differ in their treatment efficacy. Moreover, the nature of the resistance mutations that arise in patients appears to depend on the specific BTKi administered. We have previously shown that Ibrutinib binding to the kinase active site causes unanticipated long-range effects on the global conformation of BTK (Joseph, R.E., et al., 2020, https://doi.org/10.7554/eLife.60470 ). Here we show that binding of each of the five approved BTKi to the kinase active site brings about distinct allosteric changes that alter the conformational equilibrium of full-length BTK. Additionally, we provide an explanation for the resistance mutation bias observed in CLL patients treated with different BTKi and characterize the mechanism of action of two common resistance mutations: BTK T474I and L528W.
    Language English
    Publishing date 2023-12-18
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.12.18.572223
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  4. Article ; Online: Computational modeling of DLBCL predicts response to BH3-mimetics.

    Cloete, Ielyaas / Smith, Victoria M / Jackson, Ross A / Pepper, Andrea / Pepper, Chris / Vogler, Meike / Dyer, Martin J S / Mitchell, Simon

    NPJ systems biology and applications

    2023  Volume 9, Issue 1, Page(s) 23

    Abstract: In healthy cells, pro- and anti-apoptotic BCL2 family and BH3-only proteins are expressed in a delicate equilibrium. In contrast, this homeostasis is frequently perturbed in cancer cells due to the overexpression of anti-apoptotic BCL2 family proteins. ... ...

    Abstract In healthy cells, pro- and anti-apoptotic BCL2 family and BH3-only proteins are expressed in a delicate equilibrium. In contrast, this homeostasis is frequently perturbed in cancer cells due to the overexpression of anti-apoptotic BCL2 family proteins. Variability in the expression and sequestration of these proteins in Diffuse Large B cell Lymphoma (DLBCL) likely contributes to variability in response to BH3-mimetics. Successful deployment of BH3-mimetics in DLBCL requires reliable predictions of which lymphoma cells will respond. Here we show that a computational systems biology approach enables accurate prediction of the sensitivity of DLBCL cells to BH3-mimetics. We found that fractional killing of DLBCL, can be explained by cell-to-cell variability in the molecular abundances of signaling proteins. Importantly, by combining protein interaction data with a knowledge of genetic lesions in DLBCL cells, our in silico models accurately predict in vitro response to BH3-mimetics. Furthermore, through virtual DLBCL cells we predict synergistic combinations of BH3-mimetics, which we then experimentally validated. These results show that computational systems biology models of apoptotic signaling, when constrained by experimental data, can facilitate the rational assignment of efficacious targeted inhibitors in B cell malignancies, paving the way for development of more personalized approaches to treatment.
    MeSH term(s) Humans ; Proto-Oncogene Proteins c-bcl-2/genetics ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Apoptosis Regulatory Proteins/metabolism ; Apoptosis ; Computer Simulation ; Lymphoma, Large B-Cell, Diffuse/drug therapy ; Lymphoma, Large B-Cell, Diffuse/pathology
    Chemical Substances Proto-Oncogene Proteins c-bcl-2 ; Apoptosis Regulatory Proteins
    Language English
    Publishing date 2023-06-06
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2056-7189
    ISSN (online) 2056-7189
    DOI 10.1038/s41540-023-00286-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Identification of a novel form of caspase-independent cell death triggered by BH3-mimetics in diffuse large B-cell lymphoma cell lines.

    Yildirim, Nahide / Sarojam, Lakshmi / Smith, Victoria M / Pieper, Nadja M / Anders, Marius / Jackson, Ross A / Fuhrmann, Dominik C / Särchen, Vinzenz / Brücher, Daniela / Weigert, Andreas / Dyer, Martin J S / Vogler, Meike

    Cell death & disease

    2024  Volume 15, Issue 4, Page(s) 266

    Abstract: BH3-mimetics represent promising anti-cancer agents in tumors that rely on the anti-apoptotic function of B-Cell Lymphoma 2 (BCL2) proteins, particularly in leukemia and lymphoma cells primed for apoptosis. Mechanistically, BH3-mimetics may displace pro- ... ...

    Abstract BH3-mimetics represent promising anti-cancer agents in tumors that rely on the anti-apoptotic function of B-Cell Lymphoma 2 (BCL2) proteins, particularly in leukemia and lymphoma cells primed for apoptosis. Mechanistically, BH3-mimetics may displace pro-apoptotic binding partners thus inducing BAX/BAK-mediated mitochondrial permeabilization followed by cytochrome c release, activation of the caspase cascade and apoptosis. Here, we describe a novel mode of caspase-independent cell death (CICD) induced by BH3-mimetics in a subset of diffuse large B-cell lymphoma (DLBCL) cells. Of note, rather than occurring via necroptosis, CICD induced immediately after mitochondrial permeabilization was associated with transcriptional reprogramming mediated by activation of c-Jun N-terminal Kinase (JNK) signaling and Activator Protein 1 (AP1). Thereby, CICD resulted in the JNK/AP1-mediated upregulation of inflammatory chemokines and increased migration of cytotoxic Natural Killer (NK) cells. Taken together, our study describes a novel mode of CICD triggered by BH3-mimetics that may alter the immune response towards dying cells.
    MeSH term(s) Humans ; bcl-2-Associated X Protein/metabolism ; bcl-2 Homologous Antagonist-Killer Protein/metabolism ; Apoptosis ; Antineoplastic Agents/pharmacology ; Caspases ; Lymphoma, Large B-Cell, Diffuse/drug therapy ; Cell Line ; Proto-Oncogene Proteins c-bcl-2/metabolism
    Chemical Substances bcl-2-Associated X Protein ; bcl-2 Homologous Antagonist-Killer Protein ; Antineoplastic Agents ; Caspases (EC 3.4.22.-) ; Proto-Oncogene Proteins c-bcl-2
    Language English
    Publishing date 2024-04-15
    Publishing country England
    Document type Journal Article
    ZDB-ID 2541626-1
    ISSN 2041-4889 ; 2041-4889
    ISSN (online) 2041-4889
    ISSN 2041-4889
    DOI 10.1038/s41419-024-06652-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Safety and efficacy of ofatumumab in patients with fludarabine and alemtuzumab refractory chronic lymphocytic leukaemia.

    Dyer, Martin J S

    Therapeutic advances in hematology

    2013  Volume 3, Issue 4, Page(s) 199–207

    Abstract: There are now many therapeutic CD20 monoclonal antibodies undergoing clinical trials for B-cell malignancy and autoimmune conditions; which is optimal for cancer therapy is not clear. The novel human IgG1 CD20 monoclonal antibody ofatumumab has shown ... ...

    Abstract There are now many therapeutic CD20 monoclonal antibodies undergoing clinical trials for B-cell malignancy and autoimmune conditions; which is optimal for cancer therapy is not clear. The novel human IgG1 CD20 monoclonal antibody ofatumumab has shown significant activity in difficult to treat patients with chronic lymphocytic leukemia, namely those resistant or refractory to fludarabine and alemtuzumab and has now been licensed for this uncommon indication. This brief review summarizes the clinical data obtained with ofatumumab in CLL in terms of both efficacy and toxicity.
    Language English
    Publishing date 2013-03-27
    Publishing country England
    Document type Journal Article
    ZDB-ID 2585183-4
    ISSN 2040-6215 ; 2040-6207
    ISSN (online) 2040-6215
    ISSN 2040-6207
    DOI 10.1177/2040620712445329
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: The detection of chromosomal translocations involving the immunoglobulin loci in B-cell malignancies.

    Dyer, Martin J S

    Methods in molecular biology (Clifton, N.J.)

    2013  Volume 971, Page(s) 123–133

    Abstract: Chromosomal translocations involving the immunoglobulin (IG) loci are frequently seen in most subtypes of B-cell malignancy and have both diagnostic and prognostic utility. These translocations can be detected in clinical samples by several techniques ... ...

    Abstract Chromosomal translocations involving the immunoglobulin (IG) loci are frequently seen in most subtypes of B-cell malignancy and have both diagnostic and prognostic utility. These translocations can be detected in clinical samples by several techniques including metaphase cytogenetics, interphase fluorescent in situ hybridization, and a variety of PCR methods; interphase FISH is the most commonly used clinical method. Although all the common IG translocations have been identified and cloned, new IG translocations continue to be identified in both B-cell leukemia and lymphoma. It remains important to identify the involved target genes since they define novel pathogenetic drivers of disease and may represent novel therapeutic targets. This brief chapter outlines methods of detection of chromosomal translocations involving the IGHJ segments using long distance inverse (LDI) PCR and their application to clinical lymphoma samples.
    MeSH term(s) Cloning, Molecular ; DNA/chemistry ; DNA/genetics ; DNA/metabolism ; DNA Restriction Enzymes/metabolism ; Genetic Loci/genetics ; Genomics ; Humans ; Immunoglobulins/genetics ; Leukemia, B-Cell/genetics ; Leukemia, B-Cell/pathology ; Lymphoma, B-Cell/genetics ; Lymphoma, B-Cell/pathology ; Molecular Weight ; Polymerase Chain Reaction/methods ; Sequence Analysis, DNA ; Translocation, Genetic/genetics
    Chemical Substances Immunoglobulins ; DNA (9007-49-2) ; DNA Restriction Enzymes (EC 3.1.21.-)
    Language English
    Publishing date 2013
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-62703-269-8_7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Successful Treatment of Primary Cutaneous Diffuse Large B-Cell Lymphoma Leg Type With Single-Agent Venetoclax.

    Walter, Harriet S / Trethewey, Christopher S / Ahearne, Matthew J / Jackson, Ross / Jayne, Sandrine / Wagner, Simon D / Saldanha, Gerald / Dyer, Martin J S

    JCO precision oncology

    2022  Volume 3, Page(s) 1–5

    Language English
    Publishing date 2022-02-10
    Publishing country United States
    Document type Journal Article
    ISSN 2473-4284
    ISSN (online) 2473-4284
    DOI 10.1200/PO.19.00002
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Successful Retreatment With Venetoclax in a Patient With Chronic Lymphocytic Leukemia.

    Jackson, Ross A / Smith, Victoria M / Jayne, Sandrine / Drewes, Cosima / Bens, Susanne / Siebert, Reiner / Dyer, Martin J S / Walter, Harriet S

    HemaSphere

    2022  Volume 6, Issue 8, Page(s) e752

    Language English
    Publishing date 2022-07-15
    Publishing country United States
    Document type Journal Article
    ISSN 2572-9241
    ISSN (online) 2572-9241
    DOI 10.1097/HS9.0000000000000752
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: BTK mutations in patients with chronic lymphocytic leukemia receiving tirabrutinib.

    Jackson, Ross A / Britton, Robert G / Jayne, Sandrine / Lehmann, Susann / Cowley, Caroline M / Trethewey, Christopher S / Smith, Victoria M / Schmid, Ralf / Fegan, Christopher / Walter, Harriet S / Dyer, Martin J S

    Blood advances

    2023  Volume 7, Issue 14, Page(s) 3378–3381

    MeSH term(s) Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy ; Leukemia, Lymphocytic, Chronic, B-Cell/genetics ; Mutation ; Pyrimidines/therapeutic use ; Imidazoles
    Chemical Substances tirabrutinib (LXG44NDL2T) ; Pyrimidines ; Imidazoles
    Language English
    Publishing date 2023-05-29
    Publishing country United States
    Document type Research Support, Non-U.S. Gov't ; Letter
    ZDB-ID 2915908-8
    ISSN 2473-9537 ; 2473-9529
    ISSN (online) 2473-9537
    ISSN 2473-9529
    DOI 10.1182/bloodadvances.2022009366
    Database MEDical Literature Analysis and Retrieval System OnLINE

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