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Different gene sets are associated with azacitidine response in vitro and myelodysplastic syndrome patients

ABSTRACT: Different gene sets are associated with azacitidine response in vitro and myelodysplastic syndrome patients

PROVIDER: PRJNA860917 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR20340882.fastq.gz	Fastqsanger.gz
	SRR20340883.fastq.gz	Fastqsanger.gz
	SRR20340884.fastq.gz	Fastqsanger.gz
	SRR20340885.fastq.gz	Fastqsanger.gz
	SRR20340886.fastq.gz	Fastqsanger.gz

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Different gene sets are associated with azacitidine response in vitro and myelodysplastic syndrome patients

Project description:Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic disorders and characterized by dysplasia, ineffective hematopoiesis and predisposition to secondary acute myeloid leukemia (sAML). Azacitidine (AZA) is the standard care for high-risk MDS patients not eligible for allogenic bone marrow transplantation. However, only half of the patients respond and all patients eventually relapse. Response predicting biomarkers and combinatorial drugs targets enhancing response and its duration are needed. Here, we have taken a dual approach. First, we have evaluated genes encoding chromatin regulators for their capacity to modulate AZA response. We were able to validate several genes, whose genetic inhibition affected the cellular AZA response, including four genes encoding components of ISWI chromatin remodelling complex pointing towards a specific function and co-vulnerability. Second, we have used a classical cohort analysis approach measuring the association of expression of a gene panel in bone marrow samples collected at diagnosis of 36 MDS patients. The gene panel included the identified AZA modulators, genes known to be involved in AZA metabolism and previously identified candidate modulators. In addition to confirming a number of previously made observations, we were able to identify several new associations, such as SMARCA5 as positive indicator for AZA response, or NSUN3 that correlated with increased overall survival. Taken together we have identified a number of genes associated with AZA response in vitro and in patients. These groups of genes are largely non-overlapping suggesting that different gene sets need to be exploited for the development of combinatorial drug targets and response-predicting biomarkers.

2022-11-02 | GSE208736 | GEO

Analysis of chromatin accessibility relative to epigenetic features of azacitidine response in high-risk myelodysplastic syndrome

Project description:Azacitidine is used to treat patients with myelodysplastic syndrome, which alters epigenetic regulatory program that changes global gene expression by inhibiting DNA methylation. However, epigenomic factors affecting azacitidine response have not been studied in the context of chromatin. The efficacy of the hypomethylating agent differs by patient, leaving approximately 40% of patients fail to respond. Here, we demonstrate that chromatin accessibility features in patient-derived bone marrow cells can distinguish azacitidine responders from non-responders before treatment. Profiling chromatin accessibility from 23 high-risk myelodysplastic syndrome patients discovered that treatment response is strongly associated with distinct hematopoietic cell states. While non-responders showed enrichment of myeloid progenitor signatures, responders were characterized by elevated T cell populations. Notably, CD8+ T cells from non-responders exhibited selective loss of chromatin accessibility at TBX/EOMES binding sites, revealing a previously unrecognized link between T cell differentiation state and azacitidine response. These findings suggest the importance of immune cell differentiation and their activity in hypomethylating agent response for myelodysplastic syndromes, providing insights for patient stratification and treatment optimization based on the chromatin accessibility in high-risk myelodysplastic syndrome patients.

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Different Gene Sets Are Associated With Azacitidine Response In Vitro Versus in Myelodysplastic Syndrome Patients.

Project description:Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic disorders characterized by dysplasia, ineffective hematopoiesis, and predisposition to secondary acute myeloid leukemias (sAML). Azacitidine (AZA) is the standard care for high-risk MDS patients not eligible for allogenic bone marrow transplantation. However, only half of the patients respond to AZA and eventually all patients relapse. Response-predicting biomarkers and combinatorial drugs targets enhancing therapy response and its duration are needed. Here, we have taken a dual approach. First, we have evaluated genes encoding chromatin regulators for their capacity to modulate AZA response. We were able to validate several genes, whose genetic inhibition affected the cellular AZA response, including 4 genes encoding components of Imitation SWItch chromatin remodeling complex pointing toward a specific function and co-vulnerability. Second, we have used a classical cohort analysis approach measuring the expression of a gene panel in bone marrow samples from 36 MDS patients subsequently receiving AZA. The gene panel included the identified AZA modulators, genes known to be involved in AZA metabolism and previously identified candidate modulators. In addition to confirming a number of previously made observations, we were able to identify several new associations, such as NSUN3 that correlated with increased overall survival. Taken together, we have identified a number of genes associated with AZA response in vitro and in patients. These groups of genes are largely nonoverlapping suggesting that different gene sets need to be exploited for the development of combinatorial drug targets and response-predicting biomarkers.

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Analysis of chromatin accessibility relative to epigenetic features of azacitidine response in high-risk myelodysplastic syndrome

Project description:Analysis of chromatin accessibility relative to epigenetic features of azacitidine response in high-risk myelodysplastic syndrome

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Project description:Analysis of Lin-c-Kit+Sca-1- haematopoietic stem cells (HSCs) expressing the Nup98-HoxD13 (NHD13) fusion gene. NHD13 induces myelodysplastic syndrome (MDS) in mice. Results provide insight into the molecular basis of the myelodysplastic phenotype WT mouse HSCs were compared to an NHD13 mutant sequenced in triplicate on a HiSeq 2000

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Myelodysplastic syndrome: NUP98-HoxD13 (NHD13) expression effect on hematopoietic stem cells

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