Medical Biology - Research Publications

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    Caspase-2 does not play a critical role in cell death induction and bacterial clearance during Salmonella infection
    Engel, S ; Doerflinger, M ; Lee, AR ; Strasser, A ; Herold, MJ ; Bedoui, S ; Bachem, A (Springer Nature, 2021-12)
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    Emerging connectivity of programmed cell death pathways and its physiological implications
    Bedoui, S ; Herold, MJ ; Strasser, A (Nature Research, 2020-11)
    The removal of functionally dispensable, infected or potentially neoplastic cells is driven by programmed cell death (PCD) pathways, highlighting their important roles in homeostasis, host defence against pathogens, cancer and a range of other pathologies. Several types of PCD pathways have been described, including apoptosis, necroptosis and pyroptosis; they employ distinct molecular and cellular processes and differ in their outcomes, such as the capacity to trigger inflammatory responses. Recent genetic and biochemical studies have revealed remarkable flexibility in the use of these PCD pathways and indicate a considerable degree of plasticity in their molecular regulation; for example, despite having a primary role in inducing pyroptosis, inflammatory caspases can also induce apoptosis, and conversely, apoptotic stimuli can trigger pyroptosis. Intriguingly, this flexibility is most pronounced in cellular responses to infection, while apoptosis is the dominant cell death process through which organisms prevent the development of cancer. In this Review, we summarize the mechanisms of the different types of PCD and describe the physiological and pathological processes that engage crosstalk between these pathways, focusing on infections and cancer. We discuss the intriguing notion that the different types of PCD could be seen as a single, coordinated cell death system, in which the individual pathways are highly interconnected and can flexibly compensate for one another.
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    Combined absence of TRP53 target genes ZMAT3, PUMA and p21 cause a high incidence of cancer in mice
    Brennan, MS ; Brinkmann, K ; Sola, GR ; Healey, G ; Gibson, L ; Gangoda, L ; Potts, MA ; Lieschke, E ; Wilcox, S ; Strasser, A ; Herold, MJ ; Janic, A (SPRINGERNATURE, 2024-02)
    Transcriptional activation of target genes is essential for TP53-mediated tumour suppression, though the roles of the diverse TP53-activated target genes in tumour suppression remains poorly understood. Knockdown of ZMAT3, an RNA-binding zinc-finger protein involved in regulating alternative splicing, in haematopoietic cells by shRNA caused leukaemia only with the concomitant absence of the PUMA and p21, the critical effectors of TRP53-mediated apoptosis and cell cycle arrest respectively. We were interested to further investigate the role of ZMAT3 in tumour suppression beyond the haematopoietic system. Therefore, we generated Zmat3 knockout and compound gene knockout mice, lacking Zmat3 and p21, Zmat3 and Puma or all three genes. Puma-/-p21-/-Zmat3-/- triple knockout mice developed tumours at a significantly higher frequency compared to wild-type, Puma-/-Zmat3-/- or p21-/-Zmat3-/-deficient mice. Interestingly, we observed that the triple knockout and Puma-/-Zmat3-/- double deficient animals succumbed to lymphoma, while p21-/-Zmat3-/- animals developed mainly solid cancers. This analysis suggests that in addition to ZMAT3 loss, additional TRP53-regulated processes must be disabled simultaneously for TRP53-mediated tumour suppression to fail. Our findings reveal that the absence of different TRP53 regulated tumour suppressive processes changes the tumour spectrum, indicating that different TRP53 tumour suppressive pathways are more critical in different tissues.
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    Deletion of the transcriptional regulator TFAP4 accelerates c-MYC-driven lymphomagenesis
    Potts, MA ; Mizutani, S ; Garnham, AL ; Suen, CSNLW ; Kueh, AJ ; Tai, L ; Pal, M ; Strasser, A ; Herold, MJ (SPRINGERNATURE, 2023-06)
    Many lymphoid malignancies arise from deregulated c-MYC expression in cooperation with additional genetic lesions. While many of these cooperative genetic lesions have been discovered and their functions characterised, DNA sequence data of primary patient samples suggest that many more do exist. However, the nature of their contributions to c-MYC driven lymphomagenesis have not yet been investigated. We identified TFAP4 as a potent suppressor of c-MYC driven lymphoma development in a previous genome-wide CRISPR knockout screen in primary cells in vivo [1]. CRISPR deletion of TFAP4 in Eµ-MYC transgenic haematopoietic stem and progenitor cells (HSPCs) and transplantation of these manipulated HSPCs into lethally irradiated animals significantly accelerated c-MYC-driven lymphoma development. Interestingly, TFAP4 deficient Eµ-MYC lymphomas all arose at the pre-B cell stage of B cell development. This observation prompted us to characterise the transcriptional profile of pre-B cells from pre-leukaemic mice transplanted with Eµ-MYC/Cas9 HSPCs that had been transduced with sgRNAs targeting TFAP4. This analysis revealed that TFAP4 deletion reduced expression of several master regulators of B cell differentiation, such as Spi1, SpiB and Pax5, which are direct target genes of both TFAP4 and MYC. We therefore conclude that loss of TFAP4 leads to a block in differentiation during early B cell development, thereby accelerating c-MYC-driven lymphoma development.
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    Loss of TRP53 reduces but does not overcome dependency of lymphoma cells on MCL-1
    Aubrey, BJ ; Brennan, MS ; Diepstraten, ST ; Wang, Z ; Chang, C ; Herold, MJ ; Strasser, A ; Kelly, GL (SPRINGERNATURE, 2022-05)
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    Functional flexibility and plasticity in immune control of systemic Salmonella infection
    Engel, S ; Bachem, A ; Strugnell, RA ; Strasser, A ; Herold, MJ ; Bedoui, S (CURRENT BIOLOGY LTD, 2023-08)
    Immunity to systemic Salmonella infection depends on multiple effector mechanisms. Lymphocyte-derived interferon gamma (IFN-γ) enhances cell-intrinsic bactericidal capabilities to antagonize the hijacking of phagocytes as replicative niches for Salmonella. Programmed cell death (PCD) provides another means through which phagocytes fight against intracellular Salmonella. We describe remarkable levels of flexibility with which the host coordinates and adapts these responses. This involves interchangeable cellular sources of IFN-γ regulated by innate and adaptive cues, and the rewiring of PCD pathways in previously unknown ways. We discuss that such plasticity is likely the consequence of host-pathogen coevolution and raise the possibility of further functional overlap between these seemingly distinct processes.
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    Deletion of Gpatch2 does not alter Tnf expression in mice
    Dalseno, D ; Anderton, H ; Kueh, A ; Herold, MJ ; Silke, J ; Strasser, A ; Bouillet, P (SPRINGERNATURE, 2023-03-27)
    The cytokine TNF has essential roles in immune defence against diverse pathogens and, when its expression is deregulated, it can drive severe inflammatory disease. The control of TNF levels is therefore critical for normal functioning of the immune system and health. We have identified GPATCH2 as a putative repressor of Tnf expression acting post-transcriptionally through the TNF 3' UTR in a CRISPR screen for novel regulators of TNF. GPATCH2 is a proposed cancer-testis antigen with roles reported in proliferation in cell lines. However, its role in vivo has not been established. We have generated Gpatch2-/- mice on a C57BL/6 background to assess the potential of GPATCH2 as a regulator of Tnf expression. Here we provide the first insights into Gpatch2-/- animals and show that loss of GPATCH2 affects neither basal Tnf expression in mice, nor Tnf expression in intraperitoneal LPS and subcutaneous SMAC-mimetic injection models of inflammation. We detected GPATCH2 protein in mouse testis and at lower levels in several other tissues, however, the morphology of the testis and these other tissues appears normal in Gpatch2-/- animals. Gpatch2-/- mice are viable, appear grossly normal, and we did not detect notable aberrations in lymphoid tissues or blood cell composition. Collectively, our results suggest no discernible role of GPATCH2 in Tnf expression, and the absence of an overt phenotype in Gpatch2-/- mice warrants further investigation of the role of GPATCH2.
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    Generation of a CRISPR activationmouse that enables modelling of aggressive lymphoma and interrogation of venetoclax resistance (vol 13, 4739, 2022)
    Deng, Y ; Diepstraten, ST ; Potts, MA ; Giner, G ; Trezise, S ; Ng, AP ; Healey, G ; Kane, SR ; Cooray, A ; Behrens, K ; Heidersbach, A ; Kueh, AJ ; Pal, M ; Wilcox, S ; Tai, L ; Alexander, WS ; Visvader, JE ; Nutt, SL ; Strasser, A ; Haley, B ; Zhao, Q ; Kelly, GL ; Herold, MJ (NATURE PORTFOLIO, 2022-08-25)
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    Generation of a CRISPR activation mouse that enables modelling of aggressive lymphoma and interrogation of venetoclax resistance
    Deng, Y ; Diepstraten, ST ; Potts, MA ; Giner, G ; Trezise, S ; Ng, AP ; Healey, G ; Kane, SR ; Cooray, A ; Behrens, K ; Heidersbach, A ; Kueh, AJ ; Pal, M ; Wilcox, S ; Tai, L ; Alexander, WS ; Visvader, JE ; Nutt, SL ; Strasser, A ; Haley, B ; Zhao, Q ; Kelly, GL ; Herold, MJ (NATURE PORTFOLIO, 2022-08-12)
    CRISPR technologies have advanced cancer modelling in mice, but CRISPR activation (CRISPRa) methods have not been exploited in this context. We establish a CRISPRa mouse (dCas9a-SAMKI) for inducing gene expression in vivo and in vitro. Using dCas9a-SAMKI primary lymphocytes, we induce B cell restricted genes in T cells and vice versa, demonstrating the power of this system. There are limited models of aggressive double hit lymphoma. Therefore, we transactivate pro-survival BCL-2 in Eµ-MycT/+;dCas9a-SAMKI/+ haematopoietic stem and progenitor cells. Mice transplanted with these cells rapidly develop lymphomas expressing high BCL-2 and MYC. Unlike standard Eµ-Myc lymphomas, BCL-2 expressing lymphomas are highly sensitive to the BCL-2 inhibitor venetoclax. We perform genome-wide activation screens in these lymphoma cells and find a dominant role for the BCL-2 protein A1 in venetoclax resistance. Here we show the potential of our CRISPRa model for mimicking disease and providing insights into resistance mechanisms towards targeted therapies.
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    Removal of BFL-1 sensitises some melanoma cells to killing by BH3 mimetic drugs
    Gangoda, L ; Schenk, RL ; Tai, L ; Szeto, P ; Cheung, JG ; Strasser, A ; Lessene, G ; Shackleton, M ; Herold, MJ (SPRINGERNATURE, 2022-04-04)