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MEF2C phosphorylation is required for chemotherapy resistance in acute myeloid leukemia [inhibitor MRT199665]

ABSTRACT: MEF2C phosphorylation is required for chemotherapy resistance in acute myeloid leukemia [inhibitor MRT199665]

PROVIDER: PRJNA418960 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6304610.fastq.gz	Fastqsanger.gz
	SRR6304605.fastq.gz	Fastqsanger.gz
	SRR6304606.fastq.gz	Fastqsanger.gz
	SRR6304607.fastq.gz	Fastqsanger.gz
	SRR6304608.fastq.gz	Fastqsanger.gz

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MEF2C phosphorylation is required for chemotherapy resistance in acute myeloid leukemia [inhibitor MRT199665]

Project description:In acute myeloid leukemia, chemotherapy resistance remains prevalent and poorly understood. Using functional proteomics of patient AML specimens, we identified MEF2C S222 phosphorylation as a specific marker of primary chemoresistance. We found that transgenic Mef2cS222A/S222A mice engineered to block MEF2C phosphorylation exhibited normal hematopoiesis, but were resistant to leukemogenesis induced by MLL-AF9. MEF2C phosphorylation was required for leukemia stem cell maintenance, induced by MARK kinases in cells, and blocked by selective MARK inhibitor MRT199665, which caused apoptosis of MEF2C-activated human AML cell lines and primary patient specimens, but not those lacking MEF2C. These findings identify signaling-dependent dysregulation of transcription factor control as a determinant of therapy response in AML, with immediate potential for improved diagnosis and therapy for this disease.

2018-07-23 | GSE107071 | GEO

MEF2C phosphorylation is required for chemotherapy resistance in acute myeloid leukemia [mutant MEF2C]

2018-07-23 | GSE94453 | GEO

MEF2C phosphorylation is required for chemotherapy resistance in acute myeloid leukemia [ATAC-seq]

2018-07-23 | GSE107072 | GEO

MEF2C phosphorylation is required for chemotherapy resistance in acute myeloid leukemia

Project description:MEF2C phosphorylation is required for chemotherapy resistance in acute myeloid leukemia

| PRJNA418953 | ENA

MEF2C phosphorylation is required for chemotherapy resistance in acute myeloid leukemia [ATAC-seq]

Project description:MEF2C phosphorylation is required for chemotherapy resistance in acute myeloid leukemia [ATAC-seq]

| PRJNA418959 | ENA

MEF2C Phosphorylation Is Required for Chemotherapy Resistance in Acute Myeloid Leukemia.

Project description:In acute myeloid leukemia (AML), chemotherapy resistance remains prevalent and poorly understood. Using functional proteomics of patient AML specimens, we identified MEF2C S222 phosphorylation as a specific marker of primary chemoresistance. We found that Mef2cS222A/S222A knock-in mutant mice engineered to block MEF2C phosphorylation exhibited normal hematopoiesis, but were resistant to leukemogenesis induced by MLL-AF9 MEF2C phosphorylation was required for leukemia stem cell maintenance and induced by MARK kinases in cells. Treatment with the selective MARK/SIK inhibitor MRT199665 caused apoptosis and conferred chemosensitivity in MEF2C-activated human AML cell lines and primary patient specimens, but not those lacking MEF2C phosphorylation. These findings identify kinase-dependent dysregulation of transcription factor control as a determinant of therapy response in AML, with immediate potential for improved diagnosis and therapy for this disease.Significance: Functional proteomics identifies phosphorylation of MEF2C in the majority of primary chemotherapy-resistant AML. Kinase-dependent dysregulation of this transcription factor confers susceptibility to MARK/SIK kinase inhibition in preclinical models, substantiating its clinical investigation for improved diagnosis and therapy of AML. Cancer Discov; 8(4); 478-97. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 371.

| S-EPMC5882571 | biostudies-literature

MEF2C phosphorylation is required for chemotherapy resistance in acute myeloid leukemia

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

2018-07-23 | GSE107073 | GEO

Regulation of lymphoid versus myeloid fate choice by Mef2c

Project description:Despite recent advances in the identification of lymphoid-restricted progenitors, the transcription factors essential for their generation remain to be identified. Here we describe an unexpected role for the myeloid oncogene Mef2c in multipotent progenitors (MPPs), where it is required for pan-lymphoid differentiation. Mef2c deficiency was associated with profound defects in B, T, NK cell and common lymphoid progenitor production and an enhanced myeloid output. Mef2c deficiency in MPPs leads to downregulation of several key lymphoid regulators and the upregulation of the myeloid factor C/EBPa. Our studies also show that Mef2c is a critical transcriptional target of PU.1 during lymphopoiesis. Thus, Mef2c is a crucial component of the transcriptional network that regulates lymphoid specification and cell fate choice in MPPs.

2008-11-21 | GSE13686 | GEO

Homo sapiens

Project description:MEF2C phosphorylation is required for chemotherapy resistance in acute myeloid leukemia [mutant MEF2C]

| PRJNA369743 | ENA

Gene expression analysis to identify Mef2c/d target genes in B-cell progenitors

Project description:The sequential activation of distinct developmental gene networks governs the ultimate identity of a cell, but the mechanisms by which downstream programs are activated are incompletely understood. The preB-cell receptor (preBCR) is an important checkpoint of B-cell development and essential for a preB-cell to traverse into an immature B-cell. Here, we show that activation of Mef2 transcription factors by preBCR is necessary for initiating the subsequent genetic network. We demonstrate that B-cell development is blocked at the preB-cell stage in mice deficient for Mef2c and Mef2d transcription factors and that preBCR signaling enhances the transcriptional activity of Mef2c/d through phosphorylation by the ERK5 mitogen activating kinase. This activation is instrumental in inducing KrÃ¼ppel-like factor 2 and several immediate early genes of the AP1 and Egr family. Finally, we show that Mef2 proteins cooperate with the products of their target genes (Irf4 and Egr2) to induce secondary waves of transcriptional regulation. Our findings uncover a novel role for Mef2c/d in coordinating the transcriptional network that promotes early B-cell development. RNA-seq experiments were performed from Mef2c/d knockout proB-cells versus control cells to identify genes regulated by Klf2

2015-12-14 | E-GEOD-73561 | biostudies-arrayexpress

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