A novel target of CD274 involvement in AML development
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE85193 | GEO | 2017/02/14
SECONDARY ACCESSION(S): PRJNA336538
REPOSITORIES: GEO
Similar Datasets
Project description:We performed a liquid chromatography-tandem mass spectrometry analysis of endogenous TWIST1 immunoprecipitates in the LSCs isolated from MLL-AF9-driven AML mice
2022-10-09 | PXD037217 |
Project description:Epigenetic changes in cancerous cells including alterations in histone methylation facilitate the installation of growth-promoting signaling networks by altering DNA accessibility to transcriptional machinery. The oncofusion protein MLL-AF9 promotes deviant histone methylation and induces acute myelogenous leukemia (AML) in animals. Despite observations supporting a role for WNT signaling in AML pathogenesis, we have a limited mechanistic account of how cancerous growth is sustained in this context. Using chemical antagonists of WNT signaling and genetic ablation of the WNT chaperone Wntless (Wls), we identified the homeobox domain gene Sine oculis 1 (Six1) to be an atypical WNT-controlled target gene in MLL-AF9-transformed leukemic stem cells (LSCs). Elimination of Wls or Six1 in MLL-AF9 LSCs, or their exposure to WNT pathway inhibitors results in extended survival in LSC-transplanted recipient mice suggesting that WNT/SIX1 signaling is critical to MLL-AF9 transformation. Profiling of chromatin accessibility changes using ATAC-seq of MLL-AF9 transformed cells reveals chromatin remodeling in Six1 DNA regions that support binding of the transcriptional effector TCF7L2. Our data suggests de novo installation of a WNT/SIX1 signaling axis is critical to the development of some forms of AML and reveals how epigenetic alterations can re-assemble master regulatory pathways controlling cell fate with cancer-promoting consequences.
2018-03-05 | GSE111276 | GEO
Project description:Epigenetic changes in cancerous cells including alterations in histone methylation facilitate the installation of growth-promoting signaling networks by altering DNA accessibility to transcriptional machinery. The oncofusion protein MLL-AF9 promotes deviant histone methylation and induces acute myelogenous leukemia (AML) in animals. Despite observations supporting a role for WNT signaling in AML pathogenesis, we have a limited mechanistic account of how cancerous growth is sustained in this context. Using chemical antagonists of WNT signaling and genetic ablation of the WNT chaperone Wntless (Wls), we identified the homeobox domain gene Sine oculis 1 (Six1) to be an atypical WNT-controlled target gene in MLL-AF9-transformed leukemic stem cells (LSCs). Elimination of Wls or Six1 in MLL-AF9 LSCs, or their exposure to WNT pathway inhibitors results in extended survival in LSC-transplanted recipient mice suggesting that WNT/SIX1 signaling is critical to MLL-AF9 transformation. Profiling of chromatin accessibility changes using ATAC-seq of MLL-AF9 transformed cells reveals chromatin remodeling in Six1 DNA regions that support binding of the transcriptional effector TCF7L2. Our data suggests de novo installation of a WNT/SIX1 signaling axis is critical to the development of some forms of AML and reveals how epigenetic alterations can re-assemble master regulatory pathways controlling cell fate with cancer-promoting consequences.
2018-03-05 | GSE111275 | GEO
Project description:Epigenetic changes in cancerous cells including alterations in histone methylation facilitate the installation of growth-promoting signaling networks by altering DNA accessibility to transcriptional machinery. The oncofusion protein MLL-AF9 promotes deviant histone methylation and induces acute myelogenous leukemia (AML) in animals. Despite observations supporting a role for WNT signaling in AML pathogenesis, we have a limited mechanistic account of how cancerous growth is sustained in this context. Using chemical antagonists of WNT signaling and genetic ablation of the WNT chaperone Wntless (Wls), we identified the homeobox domain gene Sine oculis 1 (Six1) to be an atypical WNT-controlled target gene in MLL-AF9-transformed leukemic stem cells (LSCs). Elimination of Wls or Six1 in MLL-AF9 LSCs, or their exposure to WNT pathway inhibitors results in extended survival in LSC-transplanted recipient mice suggesting that WNT/SIX1 signaling is critical to MLL-AF9 transformation. Profiling of chromatin accessibility changes using ATAC-seq of MLL-AF9 transformed cells reveals chromatin remodeling in Six1 DNA regions that support binding of the transcriptional effector TCF7L2. Our data suggests de novo installation of a WNT/SIX1 signaling axis is critical to the development of some forms of AML and reveals how epigenetic alterations can re-assemble master regulatory pathways controlling cell fate with cancer-promoting consequences.
2018-03-05 | GSE111277 | GEO
Project description:MIR139 is a critical tumor suppressor and commonly silenced in human cancer, including acute myeloid leukemia (AML). Here, we found that depletion of identified MIR139 targets affects AML outgrowth. We unraveled the mechanism of MIR139 gene inactivation in AML expressing the Mixed-Lineage Leukemia (MLL)-AF9 oncogene. Epigenetic analyses revealed two well-conserved putative enhancer regions in close proximity of transcriptional start sites (TSS) of MIR139. These regions were silenced by the Polycomb-Repressive Complex-2 (PRC2) downstream of MLL-AF9. Genomic deletion of these regions abolished MIR139 transcriptional regulation in normal and oncogenic conditions. Genome-wide knockout screens revealed the transcriptional pausing factor of RNA Polymerase-II, POLR2M, as a critical MIR139-silencing factor. Furthermore, direct POLR2M binding to the MIR139 TSS induced paused transcription, which was abrogated upon PRC2 inhibition. We present evidence for an oncogenic POLR2M-mediated MIR139 silencing mechanism, downstream of MLL-AF9 and PRC2. Together, our findings highlight the importance of POLR2M-mediated paused transcription in AML.
2021-11-11 | PXD022488 | Pride
Project description:How the stemness of adult stem cells and cancer stem cells is regulated by environmental cues through surface receptors is poorly understood. In this gene expression analysis, we found that, in the mouse MLL-AF9 acute myeloid leukemia (AML) model, a deficiency in intracellular signaling of inhibitory receptor PIR-B resulted in increased differentiation and decreased stemness of leukemia stem cells, revealing that PIR-B supports leukemia development. Our study indicates unexpected functional significance of a classical immune inhibitory receptor in the maintenance of stemness of cancer stem cells. Total RNA obtained from wild-type MLL-AF9 LSCs compared to PirBTM MLL-AF9 LSCs
2012-03-08 | E-GEOD-36329 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE30745: Expression data from murine acute myeloid leukemia (AML) cells following shRNA-mediated suppression of Myb GSE30746: Expression data from murine Tet-off MLL-AF9/Ras acute myeloid leukemia cell lines following withdrawal of MLL-AF9 Refer to individual Series
2011-08-04 | E-GEOD-30747 | biostudies-arrayexpress
Project description:P2X7 was significantly up-regulated in leukemia patients, especially in AML (MLL-AF9) and often related to poor prognosis.We compared the transcriptomic changes in MLL-AF9 induced mouse AML and overexpressed wP2X7 in MLL-AF9 induced AML. Engaged to explore the mechanism of P2X7 in leukemia progression. Mouse AML was induced by expressing MLL-AF9 in mouse HSPCs. Leukemia cells were divided into two groups, c-kit+ and c-kit-. Due to leukemia cells were nearly 95% c-kit+ in P2X7-overexpressed AML cells, we set up four groups of leukemia cells, namely leukemia total cells (V total), leukemia c-kit positive cells (V c-kit+), leukemia c-kit negative cells (V c-kit-), overexpressed wide type P2X7 leukemia cells (wP2X7).
2021-12-29 | GSE92969 | GEO
Project description:Leukemia stem cells (LSCs) share several crucial properties with hematopoietic stem cells (HSCs) including self-renewal, cell cycle quiescence, and expression of a CD34+CD38- immunophenotype, which complicates efforts to eradicate AML by therapeutically targeting LSCs without adversely affecting HSCs. Here we report that CD93, a C-type lectin transmembrane receptor, is preferentially expressed on the cell surface of LSCs compared with HSCs in the genetic subtype of AML with genomic rearrangements of the MLL gene. LSCs that selectively express CD93 are actively cycling, and highly enriched for xeno-engraftment potential, yet comprise a minor component of an otherwise quiescent CD34+CD38- compartment of human AML. Notably, CD93 is required for LSC function in MLL leukemogenesis, and is not simply a passive surface marker co-expressed on LSCs. Thus, CD93 selectively marks and essentially maintains LSCs, and identifies them as predominantly cycling, non-quiescent leukemia-initiating cells in MLL-rearranged AML.
2015-10-02 | GSE64776 | GEO
Project description:Cyclin-dependent kinase 6 (CDK6) represents a novel therapeutic target for the treatment of certain subtypes of acute myeloid leukemia (AML). CDK4/6 kinase inhibitors have been widely studied in many cancer types and their effects may be limited by primary and secondary resistance mechanisms. CDK4/6 degraders, which eliminate kinase dependent and kinase independent effects, have been suggested as alternative therapeutic option. We show that efficacy of the CDK6 specific protein degrader BSJ-03-123 varies among AML subtypes and depends on low expression of the INK4 proteins p16INK4A and p18INK4C. INK4 protein levels are significantly elevated in MLL-AF9+ compared to AML1-ETO+ cells, contributing to the different CDK6 degradation efficacy. We demonstrate that CDK6 complexes containing p16INK4A or p18INK4C are protected from BSJ-mediated degradation and that INK4 levels define the proliferative response to CDK6 degradation. These findings define INK4 proteins as predictive marker for CDK6 degradation – targeted therapies in AML.
2022-04-04 | PXD032216 | Pride