Sir Peter MacCallum Department of Oncology - Research Publications

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    Distinct modulation of IFNγ-induced transcription by BET bromodomain and catalytic P300/CBP inhibition in breast cancer
    Hogg, SJ ; Motorna, O ; Kearney, CJ ; Derrick, EB ; House, IG ; Todorovski, I ; Kelly, MJ ; Zethoven, M ; Bromberg, KD ; Lai, A ; Beavis, PA ; Shortt, J ; Johnstone, RW ; Vervoort, SJ (BMC, 2022-12)
    BACKGROUND: Interferon gamma (IFNγ) is a pro-inflammatory cytokine that directly activates the JAK/STAT pathway. However, the temporal dynamics of chromatin remodeling and transcriptional activation initiated by IFNγ have not been systematically profiled in an unbiased manner. Herein, we integrated transcriptomic and epigenomic profiling to characterize the acute epigenetic changes induced by IFNγ stimulation in a murine breast cancer model. RESULTS: We identified de novo activation of cis-regulatory elements bound by Irf1 that were characterized by increased chromatin accessibility, differential usage of pro-inflammatory enhancers, and downstream recruitment of BET proteins and RNA polymerase II. To functionally validate this hierarchical model of IFNγ-driven transcription, we applied selective antagonists of histone acetyltransferases P300/CBP or acetyl-lysine readers of the BET family. This highlighted that histone acetylation is an antecedent event in IFNγ-driven transcription, whereby targeting of P300/CBP acetyltransferase activity but not BET inhibition could curtail the epigenetic remodeling induced by IFNγ through suppression of Irf1 transactivation. CONCLUSIONS: These data highlight the ability for epigenetic therapies to reprogram pro-inflammatory gene expression, which may have therapeutic implications for anti-tumor immunity and inflammatory diseases.
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    Targeting histone acetylation dynamics and oncogenic transcription by catalytic P300/CBP inhibition
    Hogg, SJ ; Motorna, O ; Cluse, LA ; Johanson, TM ; Coughlan, HD ; Raviram, R ; Myers, RM ; Costacurta, M ; Todorovski, I ; Pijpers, L ; Bjelosevic, S ; Williams, T ; Huskins, SN ; Kearney, CJ ; Devlin, JR ; Fan, Z ; Jabbari, JS ; Martin, BP ; Fareh, M ; Kelly, MJ ; Dupere-Richer, D ; Sandow, JJ ; Feran, B ; Knight, D ; Khong, T ; Spencer, A ; Harrison, SJ ; Gregory, G ; Wickramasinghe, VO ; Webb, A ; Taberlay, PC ; Bromberg, KD ; Lai, A ; Papenfuss, AT ; Smyth, GK ; Allan, RS ; Licht, JD ; Landau, DA ; Abdel-Wahab, O ; Shortt, J ; Vervoort, SJ ; Johnstone, RW (CELL PRESS, 2021-05-20)
    To separate causal effects of histone acetylation on chromatin accessibility and transcriptional output, we used integrated epigenomic and transcriptomic analyses following acute inhibition of major cellular lysine acetyltransferases P300 and CBP in hematological malignancies. We found that catalytic P300/CBP inhibition dynamically perturbs steady-state acetylation kinetics and suppresses oncogenic transcriptional networks in the absence of changes to chromatin accessibility. CRISPR-Cas9 screening identified NCOR1 and HDAC3 transcriptional co-repressors as the principal antagonists of P300/CBP by counteracting acetylation turnover kinetics. Finally, deacetylation of H3K27 provides nucleation sites for reciprocal methylation switching, a feature that can be exploited therapeutically by concomitant KDM6A and P300/CBP inhibition. Overall, this study indicates that the steady-state histone acetylation-methylation equilibrium functions as a molecular rheostat governing cellular transcription that is amenable to therapeutic exploitation as an anti-cancer regimen.
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    Integrated clinical and genomic evaluation of guadecitabine (SGI-110) in peripheral T-cell lymphoma
    Wong, J ; Gruber, E ; Maher, B ; Waltham, M ; Sabouri-Thompson, Z ; Jong, I ; Luong, Q ; Levy, S ; Kumar, B ; Brasacchio, D ; Jia, W ; So, J ; Skinner, H ; Lewis, A ; Hogg, SJ ; Vervoort, S ; DiCorleto, C ; Uhe, M ; Gamgee, J ; Opat, S ; Gregory, GP ; Polekhina, G ; Reynolds, J ; Hawkes, EA ; Kailainathan, G ; Gasiorowski, R ; Kats, LM ; Shortt, J (SPRINGERNATURE, 2022-06)
    Peripheral T-cell lymphoma (PTCL) is a rare, heterogenous malignancy with dismal outcomes at relapse. Hypomethylating agents (HMA) have an emerging role in PTCL, supported by shared mutations with myelodysplasia (MDS). Response rates to azacitidine in PTCL of follicular helper cell origin are promising. Guadecitabine is a decitabine analogue with efficacy in MDS. In this phase II, single-arm trial, PTCL patients received guadecitabine on days 1-5 of 28-day cycles. Primary end points were overall response rate (ORR) and safety. Translational sub-studies included cell free plasma DNA sequencing and functional genomic screening using an epigenetically-targeted CRISPR/Cas9 library to identify response predictors. Among 20 predominantly relapsed/refractory patients, the ORR was 40% (10% complete responses). Most frequent grade 3-4 adverse events were neutropenia and thrombocytopenia. At 10 months median follow-up, median progression free survival (PFS) and overall survival (OS) were 2.9 and 10.4 months respectively. RHOAG17V mutations associated with improved PFS (median 5.47 vs. 1.35 months; Wilcoxon p = 0.02, Log-Rank p = 0.06). 4/7 patients with TP53 variants responded. Deletion of the histone methyltransferase SETD2 sensitised to HMA but TET2 deletion did not. Guadecitabine conveyed an acceptable ORR and toxicity profile; decitabine analogues may provide a backbone for future combinatorial regimens co-targeting histone methyltransferases.
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    Whole genome CRISPR screening identifies TOP2B as a potential target for IMiD sensitization in multiple myeloma
    Costacurta, M ; Vervoort, SJ ; Hogg, SJ ; Martin, BP ; Johnstone, RW ; Shortt, J (FERRATA STORTI FOUNDATION, 2021-07)
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    CDK9 inhibition by dinaciclib potently suppresses Mcl-1 to induce durable apoptotic responses in aggressive MYC-driven B-cell lymphoma in vivo
    Gregory, GP ; Hogg, SJ ; Kats, LM ; Vidacs, E ; Baker, AJ ; Gilan, O ; Lefebure, M ; Martin, BP ; Dawson, MA ; Johnstone, RW ; Shortt, J (NATURE PUBLISHING GROUP, 2015-06)
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    The SMAC mimetic, LCL-161, reduces survival in aggressive MYC-driven lymphoma while promoting susceptibility to endotoxic shock
    West, AC ; Martin, BP ; Andrews, DA ; Hogg, SJ ; Banerjee, A ; Grigoriadis, G ; Johnstone, RW ; Shortt, J (NATURE PUBLISHING GROUP, 2016-04)
    Inhibitor of apoptosis proteins (IAPs) antagonize caspase activation and regulate death receptor signaling cascades. LCL-161 is a small molecule second mitochondrial activator of caspase (SMAC) mimetic, which both disengages IAPs from caspases and induces proteasomal degradation of cIAP-1 and -2, resulting in altered signaling through the NFκB pathway, enhanced TNF production and sensitization to apoptosis mediated by the extrinsic pathway. SMAC mimetics are undergoing clinical evaluation in a range of hematological malignancies. Burkitt-like lymphomas are hallmarked by a low apoptotic threshold, conveying sensitivity to a range of apoptosis-inducing stimuli. While evaluating LCL-161 in the Eμ-Myc model of aggressive Burkitt-like lymphoma, we noted unexpected resistance to apoptosis induction despite 'on-target' IAP degradation and NFκB activation. Moreover, LCL-161 treatment of lymphoma-bearing mice resulted in apparent disease acceleration concurrent to augmented inflammatory cytokine-release in the same animals. Indiscriminate exposure of lymphoma patients to SMAC mimetics may therefore be detrimental due to both unanticipated prolymphoma effects and increased susceptibility to endotoxic shock.