CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing) of paired diagnosis and relapse specimens from acute myeloid leukemia (AML) patients treated with venetoclax plus azacitidine
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE143363 | GEO | 2020/01/24
REPOSITORIES: GEO
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Project description:CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing) of paired diagnosis and relapse specimens from acute myeloid leukemia (AML) patients treated with venetoclax plus azacitidine
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Project description:To understand the role of RAS mutations in AML, we performed CITE-seq on diagnosis specimens from WT and RAS mutant AML patients.
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Project description:Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Leukemia stem cells (LSCs) drive the initiation and perpetuation of AML, are quantifiably associated with worse clinical outcomes, and often persist after conventional chemotherapy resulting in relapse1-5. In this report, we show that treatment of older patients with AML with the B cell lymphoma 2 (BCL-2) inhibitor venetoclax in combination with azacitidine results in deep and durable remissions and is superior to conventional treatments. We hypothesized that these promising clinical results were due to targeting LSCs. Analysis of LSCs from patients undergoing treatment with venetoclax + azacitidine showed disruption of the tricarboxylic acid (TCA) cycle manifested by decreased α-ketoglutarate and increased succinate levels, suggesting inhibition of electron transport chain complex II. In vitro modeling confirmed inhibition of complex II via reduced glutathionylation of succinate dehydrogenase. These metabolic perturbations suppress oxidative phosphorylation (OXPHOS), which efficiently and selectively targets LSCs. Our findings show for the first time that a therapeutic intervention can eradicate LSCs in patients with AML by disrupting the metabolic machinery driving energy metabolism, resulting in promising clinical activity in a patient population with historically poor outcomes.
2019-01-30 | GSE116481 | GEO
Project description:Determine the differences in gene expression profiles of MV-4-11 AML cells treated with HDAC1/2-selective inhibition, azacitidine, or the combination of the two agents. Acute myeloid leukemia (AML) is a heterogeneous group of hematopoietic stem cell disorders characterized by defects in myeloid differentiation and increased proliferation of neoplastic hematopoietic precursor cells. Outcomes for patients with AML remain poor, highlighting the need for novel treatment options. Aberrant epigenetic regulation plays an important role in the pathogenesis of AML, and inhibitors of DNA methyltransferase or histone deacetylase (HDAC) enzymes have exhibited activity in preclinical AML models. Combination studies with HDAC inhibitors plus DNA methyltransferase inhibitors have suggested beneficial clinical activity in AML, however the toxicity profiles of non-selective HDAC inhibitors in the combination setting limit their clinical utility. In this work, we describe the preclinical development of selective inhibitors of HDAC1 and HDAC2, which are hypothesized to have improved safety profiles, for combination therapy in AML. We demonstrate that selective inhibition of HDAC1 and HDAC2 is sufficient to achieve efficacy both as a single agent and in combination with azacitidine in preclinical models of AML, including established AML cell lines, leukemia cells from AML patient bone marrow samples and in vivo xenograft models of human AML. Gene expression profiling of AML cells treated with either an HDAC1/2 inhibitor, azacitidine, or the combination of both have identified a list of genes involved in transcription and cell cycle regulation as potential mediators of the combinatorial effects of HDAC1/2 inhibition with azacitidine. Together, these findings support the clinical evaluation of selective HDAC1/2 inhibitors in combination with azacitidine in AML patients.
2017-03-08 | GSE84440 | GEO
Project description:The nucleotide analogue azacitidine interferes with RNA and DNA metabolism and is currently the best treatment option for a subset of patients with high-risk myelodysplastic syndromes. However, only half of treated patients respond and almost all patients that initially respond eventually relapse. We performed an optimized loss-of-function shRNA screen in combination with azacitidine treatment in an MDS-derived acute myeloid leukemia cell line to identify chromatin regulators affecting drug response. We identified CBP, as a major regulator of azacitidine sensitivity. Compounds inhibiting the enzymatic activity of CBP synergistically reduced viability of MDS-derived AML cell lines when combined with AZA. Surprisingly, this effect was specific for the RNA-dependent functions of AZA and not observed with the related compound decitabine that is limited to DNA incorporation. The identification of immediate target genes suggested that the effect of CBP inhibition is mediated by downregulation of genes encoding the translational machinery, which could be confirmed in proteomic analysis of nascent proteins. Furthermore, proteins most affected by CBP inhibition include key drivers of cell cycle progression.
2021-09-10 | GSE158813 | GEO
Project description:The nucleotide analogue azacitidine interferes with RNA and DNA metabolism and is currently the best treatment option for a subset of patients with high-risk myelodysplastic syndromes. However, only half of treated patients respond and almost all patients that initially respond eventually relapse. We performed an optimized loss-of-function shRNA screen in combination with azacitidine treatment in an MDS-derived acute myeloid leukemia cell line to identify chromatin regulators affecting drug response. We identified CBP, as a major regulator of azacitidine sensitivity. Compounds inhibiting the enzymatic activity of CBP synergistically reduced viability of MDS-derived AML cell lines when combined with AZA. Surprisingly, this effect was specific for the RNA-dependent functions of AZA and not observed with the related compound decitabine that is limited to DNA incorporation. The identification of immediate target genes suggested that the effect of CBP inhibition is mediated by downregulation of genes encoding the translational machinery, which could be confirmed in proteomic analysis of nascent proteins. Furthermore, proteins most affected by CBP inhibition include key drivers of cell cycle progression.
2021-09-10 | GSE158738 | GEO
Project description:IMPRINTS-CETSA data acquisition of Kasumi-1 cells treated with Vehicle (DMSO), Venetoclax, Decitabine, Azacitidine and Azacitidine+Venetoclax using TMT 16 plex.
2024-10-23 | PXD056189 | Pride
Project description:IMPRINTS-CETSA data acquisition of Kasumi-1 cells treated with Vehicle (DMSO), Venetoclax, Decitabine, Azacitidine and Azacitidine+Venetoclax using TMT 16 plex.
2024-10-23 | PXD056183 | Pride
Project description:<p>This single-arm study design has been selected to investigate the safety of combination therapy with Vidaza® (azacitidine) and Revlimid® (lenalidomide) in a population of 18 participants with advanced MDS for the Phase I portion, and 18 participants for the Phase II portion. The multi-center nature of the study should enhance the general applicability of the results. Participants with advanced MDS were chosen because it is expected that the combination of the two drugs will by myelosuppressive, which can be considered a necessary toxicity to effect improvements in PR and CR rates in this advanced population, akin to participants with AML. Finally, the combination was chosen to be studied because currently available therapies in this population, and their effectiveness, are limited, and single-agent Vidaza® (azacitidine), while effective at delaying transformation to AML or death, is not curative.</p> <p>The doses of Revlimid® (lenalidomide) in this study are similar to those that were demonstrated to have an effect and to be well-tolerated in participants with MDS. Doses for Vidaza® (azacitidine) are similar to those used in the pivotal trial, though for a 5-day treatment period instead of 7 to minimize toxicity for the first 3 blocks of participants, and then at a lower dose over a protracted period of time to explore the safety of a 10-day treatment course.</p>
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Project description:The nucleotide analogue azacitidine (AZA) interferes with RNA and DNA metabolism and is currently the best treatment option for a subset of patients with high-risk myelodysplastic syndromes. However, only half of treated patients respond and almost all patients that initially respond eventually relapse. Thus, response-predicting biomarkers and new treatment options are urgently needed to improve the clinical management of these patients. Here, we performed a loss-of-function shRNA screen in combination with AZA treatment in a MDS-derived AML cell line to identify chromatin regulators affecting drug response. We identified the histone acetyl transferase and transcriptional co-activator CBP as a major regulator of AZA sensitivity. Compounds inhibiting the enzymatic activity of CBP synergistically reduced viability of MDS-derived AML cell lines when combined with AZA. Surprisingly, this affect was specific for the RNA-dependent functions of AZA and not observed with the related compound decitabine that is limited to DNA incorporation. The identification of immediate target genes suggested that the effect of CBP inhibition is mediated by downregulation of genes encoding the translational machinery, which could be confirmed in proteomic analysis of nascent proteins. Furthermore, proteins most affected by CBP inhibition include key drivers of cycle progression. Taken together, our results identify a novel synergistic interaction between CBP inhibitors and specifically AZA that warrants further evaluation for the combinatorial treatment of high-risk MDS patients. Beyond the scope of MDS and AZA, we provide novel insight in the function of clinically promising CBP inhibitors that is related to unexpected interference with the translational machinery.
2021-09-22 | PXD021738 | Pride