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Combination targeted therapy to disrupt aberrant oncogenic signaling and reverse epigenetic dysfunction in IDH2- and TET2-mutant acute myeloid leukemia

ABSTRACT: Combination targeted therapy to disrupt aberrant oncogenic signaling and reverse epigenetic dysfunction in IDH2- and TET2-mutant acute myeloid leukemia

PROVIDER: PRJNA313219 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR3189560.fastq.gz	Fastqsanger.gz
	SRR3189570.fastq.gz	Fastqsanger.gz
	SRR3189580.fastq.gz	Fastqsanger.gz
	SRR3189680.fastq.gz	Fastqsanger.gz
	SRR3189690.fastq.gz	Fastqsanger.gz

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Combination targeted therapy to disrupt aberrant oncogenic signaling and reverse epigenetic dysfunction in IDH2- and TET2-mutant acute myeloid leukemia (RRBS)

Project description:Genomic studies in acute myeloid leukemias (AML) have identified mutations which drive altered DNA methylation, including TET2 and IDH. Functional studies have shown these mutations contribute to transformation, although how these mutations impact the response to epigenetic therapies is not fully delineated. Here we show AMLs with TET2/IDH2 mutations combined with FLT3ITD mutations are specifically sensitive to 5-Azacytidine or to the IDH2 inhibitor AG-221, respectively. 5-Azacytidine/AG-221 therapies induced a reduction in leukemic blasts and in stem/progenitor expansion, with attenuation of aberrant DNA hypermethylation. These therapeutic benefits were achieved through restoration of differentiation, such that normalized hematopoiesis was derived from mutant cells. Consistent with these data, at the time of clinical response to 5-Azacytidine or AG-221, most patients had mutant-derived hematopoiesis. By contrast, combined AG-221/5-Azacytidine plus FLT3 inhibition reduced disease burden and reversed epigenetic dysfunction. Our studies suggest combined targeting of signaling and epigenetic pathways can increase therapeutic response in AML.

2017-02-25 | GSE78690 | GEO

Combination targeted therapy to disrupt aberrant oncogenic signaling and reverse epigenetic dysfunction in IDH2- and TET2-mutant acute myeloid leukemia (RNA-Seq)

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Combination Targeted Therapy to Disrupt Aberrant Oncogenic Signaling and Reverse Epigenetic Dysfunction in IDH2- and TET2-Mutant Acute Myeloid Leukemia.

Project description:Genomic studies in acute myeloid leukemias (AML) have identified mutations that drive altered DNA methylation, including TET2 and IDH2 Here, we show that models of AML resulting from TET2 or IDH2 mutations combined with FLT3ITD mutations are sensitive to 5-azacytidine or to the IDH2 inhibitor AG-221, respectively. 5-azacytidine and AG-221 treatment induced an attenuation of aberrant DNA methylation and transcriptional output and resulted in a reduction in leukemic blasts consistent with antileukemic activity. These therapeutic benefits were associated with restoration of leukemic cell differentiation, and the normalization of hematopoiesis was derived from mutant cells. By contrast, combining AG-221 or 5-azacytidine with FLT3 inhibition resulted in a reduction in mutant allele burden, progressive recovery of normal hematopoiesis from non-mutant stem-progenitor cells, and reversal of dysregulated DNA methylation and transcriptional output. Together, our studies suggest combined targeting of signaling and epigenetic pathways can increase therapeutic response in AML.Significance: AMLs with mutations in TET2 or IDH2 are sensitive to epigenetic therapy through inhibition of DNA methyltransferase activity by 5-azacytidine or inhibition of mutant IDH2 through AG-221. These inhibitors induce a differentiation response and can be used to inform mechanism-based combination therapy. Cancer Discov; 7(5); 494-505. ©2017 AACR.See related commentary by Thomas and Majeti, p. 459See related article by Yen et al., p. 478This article is highlighted in the In This Issue feature, p. 443.

| S-EPMC5413413 | biostudies-literature

Combination targeted therapy to disrupt aberrant oncogenic signaling and reverse epigenetic dysfunction in IDH2- and TET2-mutant acute myeloid leukemia

Project description:This SuperSeries is composed of the SubSeries listed below.

2017-02-25 | GSE78692 | GEO

Synergy between IDH2 and TET2 mutations modulates Tfh cell functional interaction with the angioimmunoblastic T-cell lymphoma microenvironment [Bisulfite-seq]

Project description:Angioimmunoblastic T-cell lymphoma (AITL) is a peripheral T-cell lymphoma that originates from T follicular helper (Tfh) cells and is characterized by a prominent tumor microenvironment (TME). IDH2 and TET2 mutations co-occur frequently in AITL but their contribution to tumorigenesis is poorly understood. We have developed an AITL mouse model that is driven by Idh2 and Tet2 mutations and in which Tfh cells exhibit aberrant transcriptomic and epigenetic programming. Neoplastic Tfh cells bearing combined Idh2 and Tet2 mutations show altered crosstalk with normal germinal center B cells that promotes B clonal expansion while decreasing Fas-FasL interaction and reducing B cell apoptosis. This altered Tfh-B cell communication could explain the unique relationship between Idh2 mutation and the prototypical AITL TME. Our mouse model also recapitulates important features of human IDH2-mutated AITL, providing a rationale for exploring the therapeutic targeting of Tfh-TME crosstalk for AITL treatment.

2023-02-01 | GSE221604 | GEO

Synergy between IDH2 and TET2 mutations modulates Tfh cell functional interaction with the angioimmunoblastic T-cell lymphoma microenvironment [ATAC-Seq]

2023-02-01 | GSE221602 | GEO

Synergy between IDH2 and TET2 mutations modulates Tfh cell functional interaction with the angioimmunoblastic T-cell lymphoma microenvironment [Tfh RNA-seq]

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Synergy between IDH2 and TET2 mutations modulates Tfh cell functional interaction with the angioimmunoblastic T-cell lymphoma microenvironment [AITL Tumor RNA-seq]

2023-02-01 | GSE221599 | GEO

Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation

Project description:Cancer-associated IDH mutations are characterized by neomorphic enzyme activity and resultant 2 hydroxyglutarate (2HG) production. Mutational and epigenetic profiling of a large AML patient cohort revealed that IDH1/2-mutant AMLs display global DNA hypermethylation and a specific hypermethylation signature. Furthermore, expression of 2HG-producing IDH alleles in cells rapidly induced global DNA hypermethylation. In the AML cohort, IDH1/2 mutations were mutually exclusive with mutations in the α-ketoglutarate-dependent enzyme TET2, and TET2 loss-of function mutations associated with similar epigenetic defects as IDH1/2 mutants. Consistent with these genetic and epigenetic data, expression of IDH mutants impaired TET2 catalytic function in cells. Finally, either expression of mutant IDH1/2 or Tet2 depletion impaired hematopoietic differentiation and increased stem cell marker expression, suggesting a shared pro-leukemogenic effect. DNA methylation and gene expression profiling in IDH1/2 mutant vs. IDH1/2 wild-type AML

2010-12-03 | E-GEOD-24505 | biostudies-arrayexpress

Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation

2010-12-03 | GSE24505 | GEO