Transcriptomic changes in SUDHL6 cells upon treatment with S63845 in the presence or abscence of active caspases
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE263183 | GEO | 2024/04/24
REPOSITORIES: GEO
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Project description:Overexpression of antiapoptotic BCL2 family proteins occurs in various hematologic malignanices and contributes to leukemogenesis by inhibiting the apoptotic machinery of the cells. BH3 mimetics provide an option for medication, with venetoclax as the first drug applied for chronic lymphocytic leukemia and for acute myeloid leukemia. To find additional hematologic entities with ectopic expression of BCL2 family members, we performed expression screening applying the LL-100 panel. Primary effusion lymphoma (PEL) and anaplastic large cell lymphoma (ALCL), 2/22 entities covered by this panel, stood out by high expression of MCL1 and low expression of BCL2. The MCL1 inhibitor AZD-5991 induced apoptosis in both malignancies suggesting that this BH3 mimetic might be efficient as drug for these diseases. The ALCL cell lines also expressed BCLXL and BCL2A1, both contributing to survival of the cells. The combination of specific BH3 mimetics yielded synergistic effects, pointing to a novel strategy for the treatment of ALCL. The PI3K/AKT inhibitor BEZ-235 could also efficiently be applied in combination with AZD-5991, providing an alternative to avoid thrombocytothemia, which is associated with the use of BCLXL inhibitors.
2021-12-31 | E-MTAB-10903 | biostudies-arrayexpress
Project description:BH3 mimetics are used as an efficient strategy to promote mitochondrial-dependent cell death in blood malignancies, including acute myeloid leukemia (AML). Venetoclax, a potent BCL2 antagonist, is used clinically in combination with hypomethylating agents for the treatment of AML, while various compounds targeting MCL1 are in clinical trials. Yet, drug resistance eventually ensues, highlighting the urgency to understand the underlying mechanisms. Our genome-wide CRISPR/Cas9 screens revealed that loss of mitophagy regulators sensitizes AML to BH3 mimetics. One such regulator is Mitofusin-2 (MFN2), a GTPase that controls mitochondrial dynamics and the degradation of damaged mitochondria through mitophagy. Resistance to BH3 mimetics is accompanied by alterations in mitochondrial morphology, enhanced mitochondria-endoplasmic reticulum interactions, and augmented mitophagy flux. MFN2 inactivation, using a novel small molecule inhibitor, and pharmacologic inhibition of mitophagy synergizes with BH3 mimetics. Overall, targeting of mitophagy along with BCL2-family members is a promising strategy to overcome drug resistance in AML.
2023-07-10 | GSE182401 | GEO
Project description:Immune checkpoint inhibitors (ICIs) are now the first line treatment for patients with advanced melanoma. Despite promising clinical results, many patients fail to respond to these therapies. BH3 mimetics, a novel class of small molecule inhibitors that bind and inhibit anti-apoptotic members of the BCL2 family proteins such as BCL2 or MCL1, have been very successful in treating hematologic malignancies. However, there are limited studies on the immunomodulatory role of the BH3 mimetics. Several factors contribute to ICI resistance including myeloid-derived suppressor cells (MDSCs) that exert immunosuppressive effects through direct and indirect inhibition of antitumor immunity. Thus, targeting MDSCs to enhance antitumor immunity has the potential to enhance the efficacy of ICIs. In this study, we show that the MCL1 inhibitor S64315 reduces melanoma tumor growth in an immune cell dependent manner in mice. Specifically, S64315 enhances antitumor immunity by reducing MDSC frequency and by promoting the activity of CD8+ T cells. Additionally, human MDSCs are 10 times more sensitive to S64315 than cutaneous melanoma lines. Further, we found that a higher expression of MCL1 is associated with poor survival for patients treated with anti-PD-1. Finally, combining S64315 and anti-PD-1 significantly slowed tumor growth compared to either agent alone. Together, this proof-of-concept study demonstrates the potential of combining MCL1 inhibitor with anti-PD-1 in the treatment of melanoma. It justifies the further development of next generation MCL1 inhibitors to improve efficacy of ICIs in treating malignant melanoma.
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Project description:Mouse models of chronic myeloid malignancies suggest that targeting mature cells of the malignant clone disrupts feedback loops that promote disease expansion. Here, we show that, in chronic myelomonocytic leukemia (CMML), monocytes that accumulate in the peripheral blood show a decreased propensity to die by apoptosis. BH3 profiling demonstrates their addiction to MCL1 (myeloid cell leukemia-1), which can be targeted with the small molecule inhibitor S63845. RNA sequencing and DNA methylation pattern analysis both point also to the implication of the MAPK (mitogen-activated protein kinase) pathway in the resistance of CMML monocytes to death and reveal an autocrine pathway in which the secreted cytokine CYTL1 (Cytokine-like protein 1) promotes ERK (extracellular signal-regulated kinase) activation through CCR2 (C-C chemokine receptor type 2). Combined MAPK and MCL1 inhibition restores apoptosis of CMML patient monocytes and reduces the expansion of patient-derived xenografts in mice. These results designate the combined inhibition of MCL1 and MAPK as a promising approach to slow down CMML progression by inducing leukemic monocyte apoptosis.
2021-01-23 | GSE165304 | GEO
Project description:Mouse models of chronic myeloid malignancies suggest that targeting mature cells of the malignant clone disrupts feedback loops that promote disease expansion. Here, we show that, in chronic myelomonocytic leukemia (CMML), monocytes that accumulate in the peripheral blood show a decreased propensity to die by apoptosis. BH3 profiling demonstrates their addiction to MCL1 (myeloid cell leukemia-1), which can be targeted with the small molecule inhibitor S63845. RNA sequencing and DNA methylation pattern analysis both point also to the implication of the MAPK (mitogen-activated protein kinase) pathway in the resistance of CMML monocytes to death and reveal an autocrine pathway in which the secreted cytokine CYTL1 (Cytokine-like protein 1) promotes ERK (extracellular signal-regulated kinase) activation through CCR2 (C-C chemokine receptor type 2). Combined MAPK and MCL1 inhibition restores apoptosis of CMML patient monocytes and reduces the expansion of patient-derived xenografts in mice. These results designate the combined inhibition of MCL1 and MAPK as a promising approach to slow down CMML progression by inducing leukemic monocyte apoptosis.
2021-01-23 | GSE165302 | GEO
Project description:MCL-1 plays a central role in B-cell lymphoma progression and drug resistance. Pharmacologically targeting MCL-1, therefore, represents an attractive strategy to combat these lymphomas. S63845, a MCL1 inhibitor, was shown to have high response rates in mantle cell lymphoma (MCL) and burkitt lymphoma.
2022-12-02 | GSE160742 | GEO
Project description:We performed RNA-seq analysis of in-house generated S63845 sensitive and resistant myeloma cell lines OPM-2 and KMS-12-BM in order to define common events in the acquisition of MCL-1 inhibitor resistance. Our results, however, point to the occurrence of cell line specific, heterogeneous paths to resistance as no common differences were observed. Subsequent experiments rather revealed that the binding kinetics of BH3 family members are a major driver of MCL-1 inhibitor resistance and that individual shifts during the establishment of resistance dependent on the baseline BH3 family profile.
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Project description:In order to establish a strict p53-dependent gene expression profile, p53 negative clones were derived from two TP53+/+ and two TP53-/mut t(4;14) human myeloma cell lines (HMCLs) using CRISPR/Cas9 technology. From the 17 dysregulated genes shared between the 6 clones from the two TP53+/+ myeloma cell lines, we established a 13-gene functional p53 score, involving genes downregulated on p53-silencing. This functional score allowed us to segregate clones, myeloma cell lines and patients’ samples according to the presence or absence of a single or double hit in TP53 gene i.e., chromosomal deletion and/or mutation. The score also distinguished 1,162 cell lines from hematological and solid cancers according to hits in TP53. Moreover, the 13-gene score was predictive of overall survival in two independent cohorts of patients. Among the 13 genes, we showed that p53-regulated BAX expression correlated to, and directly impacted, the MCL1 BH3 mimetic S63845 sensitivity of myeloma cells by modulating the amount of MCL1-BAX complexes. Resistance to cell death induced by p53-silencing was overcome by combining S63845 with venetoclax, although the synergy was significantly lower in p53-deficient versus -proficient clones and patients’ samples. Finally, by using scRNAseq analysis, we further showed in patients’ bone marrow samples that myeloma cells surviving to the BH3 mimetic combination had an about 3-fold lower p53 score. This data established a functional p53 score and showed that p53-mediating BAX expression greatly impacts mitochondria-mediated cell death in myeloma cells.
2024-04-04 | GSE245162 | GEO
Project description:In order to establish a strict p53-dependent gene expression profile, p53 negative clones were derived from two TP53+/+ and two TP53-/mut t(4;14) human myeloma cell lines (HMCLs) using CRISPR/Cas9 technology. From the 17 dysregulated genes shared between the 6 clones from the two TP53+/+ myeloma cell lines, we established a 13-gene functional p53 score, involving genes downregulated on p53-silencing. This functional score allowed us to segregate clones, myeloma cell lines and patients’ samples according to the presence or absence of a single or double hit in TP53 gene i.e., chromosomal deletion and/or mutation. The score also distinguished 1,162 cell lines from hematological and solid cancers according to hits in TP53. Moreover, the 13-gene score was predictive of overall survival in two independent cohorts of patients. Among the 13 genes, we showed that p53-regulated BAX expression correlated to, and directly impacted, the MCL1 BH3 mimetic S63845 sensitivity of myeloma cells by modulating the amount of MCL1-BAX complexes. Resistance to cell death induced by p53-silencing was overcome by combining S63845 with venetoclax, although the synergy was significantly lower in p53-deficient versus -proficient clones and patients’ samples. Finally, by using scRNAseq analysis, we further showed in patients’ bone marrow samples that myeloma cells surviving to the BH3 mimetic combination had an about 3-fold lower p53 score. This data established a functional p53 score and showed that p53-mediating BAX expression greatly impacts mitochondria-mediated cell death in myeloma cells.
2024-04-04 | GSE245049 | GEO
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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