Prediction of Venetoclax Activity in Precursor B-ALL by Functional Assessment of Apoptosis Signaling
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE123883 | GEO | 2019/08/06
REPOSITORIES: GEO
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Project description:The BCL-2 family plays important roles in acute myeloid leukemia (AML) and Venetoclax, a selective BCL-2 inhibitor, has received FDA approval for treatment of AML. However, drug resistance ensues after prolonged treatment, highlighting the need for a greater understanding of the underlying mechanisms. Using a genome-wide CRISPR/Cas9 screen in human AML, we identified genes whose inactivation sensitizes AML blasts to Venetoclax. Genes involved in mitochondrial organization and function were significantly depleted throughout our screen, including the mitochondrial chaperonin CLPB. We demonstrated that CLPB is upregulated in human AML, it is further induced upon acquisition of Venetoclax resistance and its ablation sensitizes AML cells to Venetoclax. Mechanistically, CLPB maintains the mitochondrial cristae structure via its interaction with the cristae-shaping protein OPA1, whereas its loss promotes apoptosis by inducing cristae remodeling and mitochondrial stress responses. Overall, our data suggest that targeting mitochondrial architecture may provide a promising approach to circumvent Venetoclax resistance.
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Project description:Venetoclax, a BCL-2 inhibitor, is being increasingly used in the clinic as a single agent or in combination. Thus far, there has been little to show how this drug affects the immune system. Research has been done to characterize the mechanisms of resistance of cancer cells to venetoclax, however, an immune subset of T cells called regulatory T cells has also shown resistence to apoptotic cell death via venetoclax administration. To investigate the effects of venetoclax on the transcriptional landscape of regulatory T cells (with some comparison to conventional T cells), we treated FOXP3-IRES-GFP mice for 14 days with 50mg/kg of venetoclax and analyzed their RNA profiles. We observed that Treg cells upregulate genes involved in Th17 effector cell differentiation, which was not observed in the Tcon counterparts.
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Project description:BH3 mimetics are increasingly used as anti-cancer therapeutics either alone or in conjunction with other chemotherapies. However, mounting evidence has also demonstrated that BH3 mimetics induce varied amounts of cell death in healthy immune populations. In order to maximize their clinical potential, it is essential to understand how BH3 mimetics affect discrete immune populations and to determine how BH3 mimetic pressure causes immune system adaptation. Here we focus on the BCL-2 specific inhibitor venetoclax (ABT-199) and its effects following short-term and long-term BCL-2 blockade on T cell subsets. Seven day "short-term” ex vivo and in vivo BCL-2 inhibition led to divergent cell death sensitivity patterns in CD8+ T cells, CD4+ T cells, and Tregs resulting in shifting of global T cell populations towards a more memory T cell state with increased expression of BCL-2, BCL-XL, and MCL-1. However, twenty-eight day “long-term” BCL-2 blockade during T cell engraftment following bone marrow transplantation did not lead to changes in the global T cell landscape. Despite the lack of changes in T cell proportions, animals treated with venetoclax developed CD8+ and CD4+ T cells with high levels of BCL-2 and were more resistant to apoptotic stimuli. Further, we demonstrate through RNA profiling that T cells adapt while under BCL-2 blockade post-transplant and develop a more activated genotype. Taken together, these data emphasize the importance of evaluating how BH3 mimetics affect the immune system in different treatment modalities and disease contexts and suggest that venetoclax should be further explored as an immunomodulatory compound.
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Project description:The prognosis for B cell precursor acute lymphoblastic leukemia patients with Mixed-Lineage Leukemia (MLL) gene rearrangements (MLLr BCP-ALL) is still extremely poor. Inhibition of anti-apoptotic protein BCL-2 with venetoclax emerged as a promising strategy for this subtype of BCP-ALL, however lack of sufficient responses in pre-clinical models and possibility of developing resistance exclude using venetoclax as monotherapy. Herein, we aimed to uncover potential mechanisms responsible for limited venetoclax activity in MLLr BCP-ALL and to identify drugs that could be used in combination therapy. Using RNA-seq, we observed that long-term exposure to venetoclax in vivo in patient derived xenograft model leads to downregulation of particular p53-related genes. Interestingly, addition of auranofin, a thioredoxin system inhibitor, sensitized MLLr BCP-ALL to venetoclax in various in vitro and in vivo models, independently on the p53 pathway functionality. Synergistic activity of these drugs resulted from auranofin-mediated upregulation of NOXA pro-apoptotic protein and potent induction of apoptotic cell death. More specifically, we observed that auranofin orchestrates upregulation of NOXA-encoding gene (PMAIP1) by chromatin remodeling and increased transcriptional accessibility. Altogether, these results present novel, promising drug combination that could be exploited for the treatment of MLLr BCP-ALL patients, including those with TP53 mutations.
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Project description:The prognosis for B cell precursor acute lymphoblastic leukemia patients with Mixed-Lineage Leukemia (MLL) gene rearrangements (MLLr BCP-ALL) is still extremely poor. Inhibition of anti-apoptotic protein BCL-2 with venetoclax emerged as a promising strategy for this subtype of BCP-ALL, however lack of sufficient responses in pre-clinical models and possibility of developing resistance exclude using venetoclax as monotherapy. Herein, we aimed to uncover potential mechanisms responsible for limited venetoclax activity in MLLr BCP-ALL and to identify drugs that could be used in combination therapy. Using RNA-seq, we observed that long-term exposure to venetoclax in vivo in patient derived xenograft model leads to downregulation of particular p53-related genes. Interestingly, addition of auranofin, a thioredoxin system inhibitor, sensitized MLLr BCP-ALL to venetoclax in various in vitro and in vivo models, independently on the p53 pathway functionality. Synergistic activity of these drugs resulted from auranofin-mediated upregulation of NOXA pro-apoptotic protein and potent induction of apoptotic cell death. More specifically, we observed that auranofin orchestrates upregulation of NOXA-encoding gene (PMAIP1) by chromatin remodeling and increased transcriptional accessibility. Altogether, these results present novel, promising drug combination that could be exploited for the treatment of MLLr BCP-ALL patients, including those with TP53 mutations.
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Project description:Prediction of Venetoclax Activity in Precursor B-ALL by Functional Assessment of Apoptosis Signaling
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Project description: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/+ 38 ) for inducing gene expression in vivo and in vitro. Using dCas9a-SAMKI 39 primary lymphocytes, we induced 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 transactivated pro-survival BCL-2 in Eµ-MycT/+;dCas9a-SAMKI/+ 42 haematopoietic stem and progenitor cells. Mice transplanted with these cells rapidly developed lymphomas expressing high BCL-2 and MYC. Unlike standard Eµ-Myc lymphomas, BCL-2 expressing lymphomas were highly sensitive to the BCL-2 inhibitor venetoclax. We performed genome-wide activation screens in these lymphoma cells and found a dominant role for the BCL-2 protein A1 in venetoclax resistance. Here we show the power of our CRISPRa model for mimicking disease and providing insights into resistance mechanisms towards targeted therapies.
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Project description:Natural killer (NK) cell-based immunotherapy holds promise for cancer treatment, but its efficacy is still limited, necessitating the development of new strategies. Here, we report an unexpected discovery that venetoclax, the first FDA-approved BCL-2 inhibitor, acts as an immunometabolic modulator to potentiate adoptive NK cell immunotherapy against acute myeloid leukemia (AML). Venetoclax directly activates human NK cells, boosting their cytotoxicity against AML both in vitro and in vivo, independent of BCL-2 inhibition. Venetoclax enhances NK cell binding avidity and lytic granule polarization during immunological synapse (IS) formation.Furthermore, venetoclax promotes mitochondrial respiration and ATP synthesis via the NF-κB pathway, facilitating IS formation and effector function in human NK cells.Our findings establish venetoclax as a multifaceted immunometabolic modulator that enhances NK cell function, providing new insights for augmenting NK cell-mediated cytotoxicity in cancer immunotherapy.
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