Ontology highlight
ABSTRACT:
PROVIDER: PRJNA261246 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR2142330_1.fastq.gz | Fastqsanger.gz | |||
| SRR2142330_2.fastq.gz | Fastqsanger.gz | |||
| SRR2142329_1.fastq.gz | Fastqsanger.gz | |||
| SRR2142329_2.fastq.gz | Fastqsanger.gz |
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Project description:Hematopoietic cell differentiation is required for initiation of acute myeloid leukemia [Microarray expression]
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Project description:Hematopoietic differentiation is required for initiation of acute myeloid leukemia [ATAC-seq]
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Project description:Leukemia initiating cells (LICs) of acute myeloid leukemia (AML) may arise from self-renewing hematopoietic stem cells (HSCs) and from committed progenitors. However, it remains unclear how leukemia-associated oncogenes instruct LIC formation from cells of different origins and if differentiation along the normal hematopoietic hierarchy is involved. Here, using murine models with the driver mutations MLL-AF9 or MOZ-TIF2, we found that regardless of the transformed cell types, myelomonocytic differentiation to the granulocyte macrophage progenitor (GMP) stage is critical for LIC generation. Blocking myeloid differentiation through disrupting the lineage-restricted transcription factor C/EBPa eliminates GMPs, blocks normal granulopoiesis, and prevents AML development. In contrast, restoring myeloid differentiation through inflammatory cytokines “rescues” AML transformation. Our findings identify myeloid differentiation as a critical step in LIC formation and AML development, thus guiding new therapeutic approaches. Examination of chromatin accessibility in Cebpa knock-out and control conditions.
2015-08-04 | E-GEOD-71688 | biostudies-arrayexpress
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Project description:Acute myeloid leukemia (AML) and acute T-lymphoblastic leukemia (T-ALL) maintain the undifferentiated phenotype and proliferative capacity of their respective cells of origin, hematopoietic stem/progenitor cells and immature thymocytes. The mechanisms that maintain these progenitor-like characteristics are poorly understood. We report that transcription factor Zfx is required for the development and propagation of experimental AML caused by MLL-AF9 fusion, and of T-ALL caused by Notch1 activation. In both leukemia types, Zfx activated progenitor-associated gene expression programs and prevented differentiation. Key Zfx target genes included mitochondrial enzymes Ptpmt1 and Idh2, whose overexpression partially rescued the propagation of Zfx-deficient AML. These studies identify a common mechanism that controls the cell-of-origin characteristics of acute leukemias derived from disparate lineages and transformation mechanisms. Analysis of genomic ZFX binding in the AML cell line NOMO-1 and the T-ALL cell line RPMI-8402
2014-01-30 | E-GEOD-43147 | biostudies-arrayexpress
Project description:Epigenetic mechanisms, including acetylation, phosphorylation, and methylation of nucleosomal histones, contribute greatly to physiological control of gene expression required for hematopoietic cell differentiation. Perturbations in histone methylation patterns and mutations in histone methyltransferases and demethylases are frequently identified in acute lymphoid and myeloid leukemia. Histone H3 methylation patterns on lysine 4 and 27 residues define bivalent, or poised, chromatin in the embryonic and hematopoietic stem cells. We examined how the bivalent histone methylation patterns change through differentiation from an embryonic stem cell to a hematopoietic stem cell, and followed these changes through malignant lymphoid and myeloid hematopoiesis. Using an integrative bioinformatics analysis of genome-wide histone methylation patterns, we find that a common bivalent histone methylation pattern does not exist for lymphoid or myeloid leukemia. Instead, a select subset of key hematopoietic genes retains the activating H3K4 trimethyl mark in leukemia cells when compared with hematopoietic stem cells. A close examination of genes marked for active transcription suggests that the malignant transcriptional program is dictated primarily by the cytogenetics and the mutations present in leukemia subtypes. Our findings have implications in determining the treatment for leukemia using epigenetic inhibitors, particularly for those malignancies with a mixed immunophenotype.
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2020-12-26 | PXD023317 |
Project description:The histone-3 lysine-4 methyltransferase KMT2D is frequently mutated in human cancers. However, knowledge of its role in the initiation and maintenance of acute myeloid leukemia (AML) is incomplete. Here, we show that KMT2D is generally downregulated in human AML. Using shRNA and CRISPR/Cas9 technologies, we show that Kmt2d loss, by cooperating with Trp53 and Nf1 loss, promoted mouse acute myeloid leukemogenesis through a differentiation block of hematopoietic stem and progenitor cells. Furthermore, using a doxycycline-induced shRNA system, we show that restoring Kmt2d impairs AML maintenance. Multi-omics analyses of Kmt2d-deficient and -restored AML cells showed that Kmt2d, via histone methyltransferase activity and chromatin remodeling, epigenetically regulates the expression of genes controlling hematopoietic stem cell differentiation. Lastly, we showed that 3-Deazaneplanocin A, a histone methyltransferase EZH2 inhibitor, could specifically repress Kmt2d-deficient AML cell growth and reverse pro-leukemia programs. Thus, our study indicate Kmt2d is a tumor suppressor, whose downregulation promotes AML development through differentiation blockage.
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| phs000549 | dbGaP