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Modelling acquired resistance to DOT1L inhibition exhibits the adaptive potential of KMT2A-rearranged Acute Lymphoblastic Leukemia’

ABSTRACT: Modelling acquired resistance to DOT1L inhibition exhibits the adaptive potential of KMT2A-rearranged Acute Lymphoblastic Leukemia’

PROVIDER: PRJNA962684 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24326936_1.fastq.gz	Fastqsanger.gz
	SRR24326936_2.fastq.gz	Fastqsanger.gz
	SRR24326937_1.fastq.gz	Fastqsanger.gz
	SRR24326937_2.fastq.gz	Fastqsanger.gz
	SRR24326938_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Modelling acquired resistance to DOT1L inhibition exhibits the adaptive potential of KMT2A-rearranged Acute Lymphoblastic Leukemia’ [RNA-seq]

Project description:KMT2A-rearranged acute lymphoblastic leukemia (ALL) is an aggressive type of leukemia which represents the most common form diagnosed in infancy. Oncogenic KMT2A-fusion proteins recruit histone methyltransferase DOT1L which leads to misplaced H3K79 methylation inducing an abnormal transcriptomic landscape that favors leukemia development. Hence, inhibition of DOT1L represents an attractive therapeutic strategy. Unfortunately, the first-in-class DOT1L inhibitor pinometostat resulted in the development of resistance. To understand this resistance we established acquired resistance to DOT1L inhibition in a pediatric KMT2A::AFF1+ B-ALL cell line model that stably became ~35-fold more resistant to pinometostat. Interestingly, while becoming almost completely independent of DOT1L-mediated H3K79 methylation, these cells remained fully dependent on the physical presence of DOT1L, HOXA9, as well as the KMT2A::AFF1 fusion protein. Further characterization of these cells using RNA-, ChIP-, and ATAC-sequencing analyses revealed that acquired resistance to DOT1L inhibition leads to a selective loss of KMT2A-fusion driven epigenetic regulation and expression of genes such as PROM1 (encoding the hematopoietic/leukemia stem cell marker CD133) and its enhancer TAPT1, as well as other putative KMT2A::AFF1 target genes such as RUNX2, PRSS12, ZC3H12, and GNAQ. In contrast, the levels of H3K79me2 and expression of other KMT2A::AFF1 target genes, including HOXA9, MEIS1, and CDK6 remained unaffected. Concomitantly, pinometostat-resistant KMT2A::AFF1+ B-ALL cells showed upregulation of genes associated with a myeloid immunophenotype, including CD33, LILRB4/CD85k, MPEG1, CCL5, and LIMK1. Taken together, we here present a valuable model to study the adaptive potential of KMT2A-rearranged ALL upon losing dependency on one of its main oncogenic properties.

2023-09-27 | GSE230791 | GEO

Modelling acquired resistance to DOT1L inhibition exhibits the adaptive potential of KMT2A-rearranged Acute Lymphoblastic Leukemia’ [ATAC-seq]

2023-09-27 | GSE230799 | GEO

Modelling acquired resistance to DOT1L inhibition exhibits the adaptive potential of KMT2A-rearranged Acute Lymphoblastic Leukemia’ [ChIP-seq]

2023-09-27 | GSE230806 | GEO

Modelling acquired resistance to DOT1L inhibition exhibits the adaptive potential of KMT2A-rearranged Acute Lymphoblastic Leukemia’ [ChIP-seq]

Project description:Modelling acquired resistance to DOT1L inhibition exhibits the adaptive potential of KMT2A-rearranged Acute Lymphoblastic Leukemia’ [ChIP-seq]

| PRJNA962573 | ENA

Modelling acquired resistance to DOT1L inhibition exhibits the adaptive potential of KMT2A-rearranged Acute Lymphoblastic Leukemia’ [RNA-seq]

Project description:Modelling acquired resistance to DOT1L inhibition exhibits the adaptive potential of KMT2A-rearranged Acute Lymphoblastic Leukemia’ [RNA-seq]

| PRJNA962586 | ENA

Modelling acquired resistance to DOT1L inhibition exhibits the adaptive potential of KMT2A-rearranged Acute Lymphoblastic Leukemia’ [ATAC-seq]

Project description:Modelling acquired resistance to DOT1L inhibition exhibits the adaptive potential of KMT2A-rearranged Acute Lymphoblastic Leukemia’ [ATAC-seq]

| PRJNA962578 | ENA

RNA-seq analysis of human KMT2A rearranged Molm14 AML cell line treated with DOT1L and/or EZH2 inhibitor

Project description:The histone methyltransferases DOT1L (H3K79me1,2,3 KMT, "activating" chromatin mark) and EZH2 (H3K27me1,2,3 KMT, "silencing" mark) have both been shown to be required for growth and survival of KMT2A rearranged AML cells. Both KMTs have been shown to modulate expression of HOXA cluster genes, albeit for EZH2 this has not been shown in the context of KMT2A rearranged AML, but in other subtypes of AML. We asked what transcriptional effects dual inhibition of DOT1L and EZH2 has in KMT2A rearranged AML.

2020-04-29 | GSE149520 | GEO

RNA-seq analysis of human KMT2A rearranged MV4;11 AML cell line treated with DOT1L and/or EZH2 inhibitor

2019-07-17 | GSE134369 | GEO

Phosphoproteomics of primary acute myeloid leukemia cells with rearranged KMT2A

Project description:Acute myeloid leukemia (AML) is a disease with poor outcome but patients harbouring certain chromosomal rearrangements or complex karyotypes have particularly adverse prognosis. For these patients, targeted therapies have not yet made a significant clinical impact. To understand the molecular landscape of poor risk AML we profiled 55 poor risk AML patients using a multiomics approach that included transcriptomics (n=39), proteomics (n=55), phosphoproteomics (n=55) and an ex vivo drug sensitivity screening (482 compounds tested in at least 30 patients). We identified a phosphoproteomics signature that define two biologically distinct groups of KMT2A rearranged leukaemia, which we term MLLGA and MLLGB. MLLGA presented increased DOT1L phosphorylation, HOXA gene expression, CDK1 activity and phosphorylation of proteins involved in RNA metabolism, replication and DNA damage when compared to MLLGB and no KMT2A rearranged samples. MLLGA was particularly sensitive to 15 compounds including genotoxic drugs and inhibitors of mitotic kinases and IMPDH relative to other cases. The expression of IMPDH2 and multiple nucleolar proteins was higher in MLLGA and correlated with the response to IMPDH inhibition in KMT2A rearranged leukaemia, suggesting a role of the nucleolar activity in sensitivity to IMPDH inhibition. In summary, our multilayer molecular profiling of poor risk AML matched to the response to hundreds of compounds identified a phosphoproteomics signature that define two biologically and phenotypically distinct groups of KMT2A rearranged leukaemia. These data provide a rationale for the development of specific therapies for KMT2A subgroups characterised by the MLLGA phosphoproteomics signature identified in this study.

2023-03-11 | PXD036669 | Pride

RNA-seq analysis of murine KMT2A-MLLT3 with DOT1L overexpressed

Project description:We transduced two individual murine KMT2A-MLLT3 AML samples with DOT1L and three days after sorting for DOT1L+ cells collected for RNA-seq MLL-rearranged leukemias have been previously shown to be dependent on the presence of histone 3 lysine 79 (H3K79) dimethylation on the genomic targets of the fusion, and an inhibitor of the H3K79 methyltransferase DOT1L is in clinical trials for MLL-rearranged leukemia. In order to ask what biologic effects overexpression of DOT1L would have on the H3K79me2 ChIP-Seq profiles and MLL-fusion target gene expression, murine leukemias generated by transplanting MSCV-MLL-AF9-GFP transduced lin- cKit+ Sca1+ bone marrow cells were subjected to overexpression of DOT1L. Cells were sorted into low (low level of DOT1L overexpression), high (high level of DOT1L overexpression) and bulk (entire population) samples, and subjected to H3K79me2 ChIP-Seq (using a drosophila spike in for normalization) and RNA-Seq analysis 3 days after transduction.

2019-07-10 | GSE134035 | GEO

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