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Lineage tracing of acute myeloid leukemia reveals the impact of hypomethylating agents on chemoresistance selection

ABSTRACT: Lineage tracing of acute myeloid leukemia reveals the impact of hypomethylating agents on chemoresistance selection

PROVIDER: PRJNA555350 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR9709050_1.fastq.gz	Fastqsanger.gz
	SRR9709050_2.fastq.gz	Fastqsanger.gz
	SRR9709051_1.fastq.gz	Fastqsanger.gz
	SRR9709051_2.fastq.gz	Fastqsanger.gz
	SRR9709052_1.fastq.gz	Fastqsanger.gz

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Lineage tracing of acute myeloid leukemia reveals the impact of hypomethylating agents on chemoresistance selection

Project description:Chemotherapy-resistant cancer recurrence is a major cause of mortality. In acute myeloid leukemia (AML), chemorefractory relapses result from the complex interplay between altered genetic, epigenetic and transcriptional states in leukemic cells. We developed an experimental model system using in vitro lineage tracing coupled with exome, transcriptome and in vivo functional readouts to assess the AML population dynamics and associated molecular determinants underpinning chemoresistance development. We found that combining standard chemotherapeutic regimens with low doses of DNA methyltransferase inhibitors (DNMTi, hypomethylating drugs) prevents chemoresistant relapses. Mechanistically, DNMTi suppressed the outgrowth of a pre-determined set of chemoresistant AML clones with stemness properties, instead favoring the expansion of rarer and unfit chemosensitive clones. Importantly, we confirmed the capacity of DNMTi combination to suppress stemness-dependent chemoresistance development in both xenotransplantation models and primary AML patient samples. Together, these results support the potential of DNMTi combination treatment to circumvent the development of chemorefractory AML relapses.

2019-07-19 | GSE134506 | GEO

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Lineage tracing of acute myeloid leukemia reveals the impact of hypomethylating agents on chemoresistance selection.

Project description:Chemotherapy-resistant cancer recurrence is a major cause of mortality. In acute myeloid leukemia (AML), chemorefractory relapses result from the complex interplay between altered genetic, epigenetic and transcriptional states in leukemic cells. Here, we develop an experimental model system using in vitro lineage tracing coupled with exome, transcriptome and in vivo functional readouts to assess the AML population dynamics and associated molecular determinants underpinning chemoresistance development. We find that combining standard chemotherapeutic regimens with low doses of DNA methyltransferase inhibitors (DNMTi, hypomethylating drugs) prevents chemoresistant relapses. Mechanistically, DNMTi suppresses the outgrowth of a pre-determined set of chemoresistant AML clones with stemness properties, instead favoring the expansion of rarer and unfit chemosensitive clones. Importantly, we confirm the capacity of DNMTi combination to suppress stemness-dependent chemoresistance development in xenotransplantation models and primary AML patient samples. Together, these results support the potential of DNMTi combination treatment to circumvent the development of chemorefractory AML relapses.

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Project description:Lineage tracing of acute myeloid leukemia reveals the impact of hypomethylating agents on chemoresistance selection

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SETD2 loss sensitizes kidney cancer cells to DNA hypomethylating agents

Project description:SETD2 loss sensitizes kidney cancer cells to DNA hypomethylating agents

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Hypomethylating agents sensitize diffuse large B-cell lymphoma to venetoclax

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SETD2 loss sensitizes kidney cancer cells to DNA hypomethylating agents

Project description:Large-scale sequencing efforts in Clear cell renal cell carcinoma (ccRCC) have found a high prevalence of mutations in chromatin-related genes. Prominent within this group is SETD2, which is mutated in 15% of ccRCC and is associated with aggressive disease. SETD2 is a methyltransferase responsible for trimethylating lysine 36 on histone H3 (H3K36me3). Although it is not completely understood how SETD2 loss contributes to ccRCC tumorigenesis, it is thought that it reprograms the epigenetic landscape of the cell. Here we explore the impact that SETD2/H3K36me3 loss has on the DNA methylome in ccRCC cells. DNA methylation was measured using the EPIC DNA methylation assay in 786-O ccRCC cells and non-cancerous transformed proximal tubule kidney cells (HKC) with and without SETD2. Sensitivity to DNA hypomethylating agents was assessed by dose-response assay using 5-aza-2'-deoxycytidine. Apoptosis was measured via Annexin-V/PI staining by flow cytometry. Mitochondrial fitness was evaluated by electron microscopy and flow cytometry. Moreover, activity of 5-aza-2'-deoxycytidine, a DNA hypomethylating agent, in was assessed in SETD2 WT/KO xenografts in NOD-Scid mice. SETD2 loss resulted in DNA hypermethylation in HKC cells and to a greater extent in 786-O. Dose-response assays showed that SETD2-null ccRCC cells are sensitive to 5-aza-2'-deoxycytidine. Furthermore, Annexin-V/PI staining revealed more apoptotic and necrotic cells in SETD2-null cells following 5-aza-2'-deoxycytidine treatment, which was rescued using a Caspase inhibitor. In addition, 5-aza-2'-deoxycytidine induced profound changes in mitochondria in SETD2-null cells, including loss of membrane potential and size reduction. Indeed, in vivo experiments verified increased SETD2-null xenografts’ sensitivity to 5-aza-2'-deoxycytidine. We show that SETD2 loss in ccRCC cells causes DNA hypermethylation, creating a synthetic lethal dependency with DNA hypomethylating agents.

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SETD2 loss sensitizes kidney cancer cells to DNA hypomethylating agents [methylation]

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DNA hypomethylating agents increase activation and cytolytic activity of CD8+ T-cells

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DNA hypomethylating agents increase activation and cytolytic activity of CD8+ T-cells

Project description:DNA hypomethylating agents (HMAs) induce Type I/III interferon signaling through dsRNA-mediated viral mimicry in cancer cells. Yet, the direct effects of HMAs in immune cells remains less clear. Here, we demonstrate that HMA treatments can directly modulate the anti-tumor response and effector function of CD8+ T-cells. In vivo HMA treatment promotes CD8+ T-cell tumor infiltration and supresses tumor growth via CD8+ T-cell dependent activity. HMAs enhances primary human CD8+ T-cells activation markers, effector cytokine production, and anti-tumor cytolytic activity. Epigenomic and transcriptomic profiling shows that HMAs vastly regulate T-cell activation related transcriptional networks, culminating with over-activation of NFATc1 short-isoforms. Mechanistically, demethylation of an intragenic CpG Island immediately downstream to the 3'UTR of the short isoform was associated with anti-sense transcription and alternative polyadenylation of NFATc1 short-isoforms. High-dimensional single-cell mass cytometry (CyTOF) analyses reveal a selective effect of HMAs on a subset of human CD8+ T-cell subpopulations, resulting in an increase in both number and abundance of a granzymeBhigh, perforinhigh effector subpopulation. Overall, our findings support the use of HMAs as a therapeutic strategy to boost anti-tumor immune response.

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