Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA172041 | ENA |
REPOSITORIES: ENA
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Project description:Gene expression profiling of Acute Myeloid Leukemia (AML) samples
| PRJNA150437 | ENA
Project description:The drug efflux pump ABCB1 is a key driver of chemoresistance, and high expression predicts for treatment failure in acute myeloid leukemia (AML). We show that both acute and chronic exposure of leukemia cells to daunorubicin activates an integrated stress response-like transcriptional program to induce ABCB1 through remodeling and dynamic activation of an ATF4-bound, stress-responsive enhancer. In primary human AML, stress-responsive ABCB1 enhancers are accessible and acetylated, and exposure of fresh blast cells to daunorubicin induces ABCB1 in a dose-dependent manner. Dynamic induction of ABCB1 by diverse stressors, including chemotherapy, facilitates escape of leukemia cells from targeted third-generation ABCB1 inhibition. Stress-induced up regulation of ABCB1 is mitigated by combined use of pharmacologic inhibitors U0126 and ISRIB, which inhibit stress signaling.
2020-02-03 | GSE131824 | GEO
Project description:Leukemia is characterized by genetic and epigenetic mutations resulting in selection of cancer stem cells, which are unable to differentiate. While genetic alterations are difficult to target, the epigenome is intrinsically dynamic and readily offers new therapeutic strategies. Thus, identifying cancer-specific context-dependent targets and unraveling their biological function may open up new therapeutic perspectives. Here, we identify bromodomain-containing protein 9 (BRD9) as a critical target required in acute myeloid leukemia (AML). We show that BRD9 is overexpressed in AML cells including ex vivo primary blasts compared to CD34+. By targeting BRD9 expression in AML, we observed an alteration in proliferation and survival, ultimately resulting in the induction of apoptosis. Intriguingly, genome-wide profiling revealed that BRD9 binds enhancer regions in a cell type-specific manner, regulating cell type-related processes. We unveil a novel BRD9-sustained STAT5 pathway activation via regulation of SOC3 expression levels. Our findings identify a previously undescribed BRD9-STAT5 axis as critical for leukemia maintenance, suggesting BRD9 as a potential therapeutic target.
2019-11-11 | PXD013245 | Pride
Project description:The bromodomain and extraterminal (BET) protein BRD4 is a therapeutic target in acute myeloid leukemia (AML). Here, we demonstrate that the AML maintenance function of BRD4 requires its interaction with NSD3, which belongs to a subfamily of H3K36 methyltransferases. Unexpectedly, AML cells were found to only require a short isoform of NSD3 that lacks the methyltransferase domain. We show that NSD3-short is an adaptor protein that sustains leukemia by linking BRD4 to the CHD8 chromatin remodeler, by using a PWWP chromatin reader module, and by employing an acidic transactivation domain. Genetic targeting of NSD3 or CHD8 mimics the phenotypic and transcriptional effects of BRD4 inhibition. Furthermore, BRD4, NSD3, and CHD8 colocalize across the AML genome, and each is released from super-enhancer regions upon chemical inhibition of BET bromodomains. These findings suggest that BET inhibitors exert therapeutic effects in leukemia by evicting BRD4-NSD3-CHD8 complexes from chromatin to suppress transcription. ChIP-Seq for regulatory factors of BRD4, NSD3, CHD8 and histone modification H3K36me2 in MLL-AF9 transformed acute myeloid leukemia cells (RN2)
2015-12-17 | E-GEOD-71183 | biostudies-arrayexpress
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:Differentiating agents have been proposed to overcome the impaired cellular differentiation in acute myeloid leukemia (AML). However, only the combinations of all-trans retinoic acid or arsenic trioxide with chemotherapy have been successful, and only in treating acute promyelocytic leukemia (also called AML3). Here we showed that iron homeostasis is an effective target in the treatment of AML. Iron chelating therapy induces the differentiation of leukemia blasts and normal bone marrow precursors into monocytes/macrophages in a manner involving modulation of reactive oxygen species expression and the activation of mitogen-activated protein kinases (MAPK). Thirty percent of the genes most strongly induced by iron deprivation are also targeted by vitamin D3 (VD), a well-known differentiating agent. Iron chelating agents induce expression and phosphorylation of the VD receptor, and iron deprivation and VD act synergistically. VD magnifies activation of MAPK JNK and the induction of VD receptor target genes. When used to treat one AML patient refractory to chemotherapy, the combination of iron chelating agents and VD resulted in reversal of pancytopenia and blast differentiation. We propose that iron availability modulates myeloid cell commitment, and that targeting this cellular differentiation pathway together with conventional differentiating agents provides new therapeutic modalities for AML. This study presents 8 arrays 4x44K Agilent.
2010-03-23 | E-TABM-925 | biostudies-arrayexpress
Project description:The key myeloid transcription factor (TF) CEBPA is frequently mutated in acute myeloid leukemia (AML), but the molecular ramifications of this leukemic driver mutation remain elusive. To investigate CEBPA mutant AML, we compared gene expression changes in human CEBPA mutant AML and in the corresponding CebpaLp30 mouse model, and identified a conserved cross-species transcriptional program. ChIP-seq revealed aberrantly activated enhancers, exclusively occupied by the leukemia-associated CEBPA-p30 isoform. One leukemic-enhancer upstream of Nt5e, encoding CD73, was physically and functionally linked to this conserved AML gene, and could be activated by CEBPA. Targeting of CD73-adenosine signaling increased AML survival in transplanted mice. Our data indicate a first-in-class link between a TF cancer driver mutation and a druggable, direct transcriptional target.
2019-08-08 | PXD011359 | Pride