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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. [ABSTRACT FROM AUTHOR]

Summary The chromosomal translocation t(1;6)(p35.3;p25.2) is a rare but recurrent aberration in chronic lymphocytic leukaemia (CLL). We report molecular characterization of 10 cases and show that this translocation juxtaposes interferon regulatory factor 4 (IRF4) on 6p25 with regulator of chromosome condensation 1 (RCC1) on 1p35. The breakpoints fell within the 5′ untranslated regions of both genes, resulting in RCC1::IRF4 fusion transcripts without alterations of the protein‐coding sequences. Levels of expression of both RCC1 and IRF4 proteins were not obviously deregulated. The cases showed other mutations typical of CLL and we confirm previously reported skewing towards the IGHV‐unmutated subtype. RCC1::IRF4 fusion characterizes a rare subset of CLL. [ABSTRACT FROM AUTHOR]

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.

The phase III GALLIUM trial assessed the safety and efficacy of obinutuzumab-based versus rituximab-based immunochemotherapy in patients with previously untreated follicular lymphoma (FL) or marginal zone lymphoma (MZL). At the primary analysis, the trial met its primary end point, demonstrating improvement in investigator-assessed progression-free survival (PFS) with obinutuzumab-based versus rituximab-based immunochemotherapy in patients with FL. We report the results of the final analysis in the FL population, with an additional exploratory analysis in the MZL subgroup. Overall, 1202 patients with FL were randomized 1:1 to obinutuzumab- or rituximab-based immunochemotherapy followed by maintenance with the same antibody for up to 2 years. After a median 7.9 (range, 0.0-9.8) years of follow-up, PFS remained improved with obinutuzumab- versus rituximab-based immunochemotherapy, with 7-year PFS rates of 63.4% versus 55.7% ( P = 0.006). Time-to-next antilymphoma treatment was also improved (74.1% versus 65.4% of patients had not started their next antilymphoma treatment at 7 y; P = 0.001). Overall survival was similar between the arms (88.5% versus 87.2%; P = 0.36). Irrespective of the treatment received, PFS and OS were higher in patients with a complete molecular response (CMR) versus those with no CMR ( P < 0.001). Serious adverse events were reported in 48.9% and 43.4% of patients in the obinutuzumab and rituximab arms, respectively; there was no difference in the rate of fatal adverse events (4.4% and 4.5%, respectively). No new safety signals were reported. These data demonstrate the long-term benefit of obinutuzumab-based immunochemotherapy and confirm its role as a standard-of-care for the first-line treatment of advanced-stage FL, taking into account patient characteristics and safety considerations., Competing Interests: WT reports honoraria from F. Hoffmann-La Roche Ltd, Gilead Sciences, and Bristol-Myers Squibb, consultancy fees from F. Hoffmann-La Roche Ltd, Bristol-Myers Squibb, Incyte, and Takeda, and travel and conference registration fees from F. Hoffmann-La Roche Ltd, Gilead Sciences, and Takeda. WH reports honoraria from F. Hoffmann-La Roche Ltd, Janssen, Gilead Sciences and Celgene; a consulting/advisory role for F. Hoffmann-La Roche Ltd, Janssen and Gilead Sciences; speakers’ bureau for F. Hoffmann-La Roche Ltd, Janssen and Gilead Sciences; research funding from F. Hoffmann-La Roche Ltd, Janssen and Bayer; and travel expenses/accommodation from F. Hoffmann-La Roche Ltd, Janssen and Gilead Sciences. CB reports honoraria and speakers’ bureau fees from, and a consulting/advisory role for F. Hoffmann-La Roche Ltd, Pfizer, Janssen, Hexal, Celltrion Healthcare, AbbVie, Novartis, Bayer, MorphoSys, Regeneron Pharmaceuticals, and BeiGene; and research funding from F. Hoffmann-La Roche Ltd, Janssen, Celltrion Healthcare, AbbVie, Bayer, Amgen, and MSD. GC reports a consultancy role for F. Hoffmann-La Roche Ltd and Celgene; and honoraria from Bristol-Myers Squibb, Sanofi, Janssen, Gilead Sciences, AbbVie, Takeda, F. Hoffmann-La Roche Ltd, and Celgene. DC acknowledges support and funding from the Royal Marsden NIHR Biomedical Research Center. MJSD reports research funding from F. Hoffmann-La Roche Ltd. JGG reports grants and personal fees from Celgene, AstraZeneca and Janssen; and personal fees from AbbVie, Gilead, Karyopharm, MorphoSys, Novartis, and T.G. Therapeutics.EP reports speakers’ fees from Gilead Sciences, advisory board fees from BeiGene, virtual conference attendance fees from Celgene, and travel and conference registration fees from Takeda. MD reports research funding from AbbVie, Bayer, Bristol-Myers Squibb/Celgene, Gilead Sciences/Kite, Janssen, and F. Hoffmann-La Roche Ltd; honoraria from Amgen, AstraZeneca, Gilead Sciences/Kite, Janssen, Lilly, Novartis, and F. Hoffmann-La Roche Ltd; and membership on an entity’s Board of Directors or advisory committees for AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Gilead Sciences/Kite, Janssen, Lilly/Loxo Oncology, Novartis, and F. Hoffmann-La Roche Ltd. JFS reports speakers’ bureau fees, advisory board fees, and research funding from AbbVie, advisory board fees from AstraZeneca, advisory board fees from BeiGene, advisory board fees and research funding from Bristol-Myers Squibb, scientific advisory board membership from Genor Biopharma, advisory board fees from Gilead, advisory board fees and research funding from Janssen, advisory board fees, speakers’ bureau fees, research funding and expert testimony fees from F. Hoffmann-La Roche Ltd, and advisory and expert testimony fees from TG Therapeutics. JT reports research funding from F. Hoffmann-La Roche Ltd, Celgene, Janssen, PCYC, and BeiGene. DK, TGN, and AK is employed by and has equity ownership interests in F. Hoffmann-La Roche Ltd. MH reports a consultancy/advisory role with Celgene, Gilead, and F. Hoffmann-La Roche Ltd and research funding from F. Hoffmann-La Roche Ltd. RM reports honoraria from F. Hoffmann-La Roche Ltd and Janssen. All the other authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)