ATACseq analysis of M07e cells and patient derived AMKL cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA543761 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9090560_1.fastq.gz | Fastqsanger.gz | |||
| SRR9090560_2.fastq.gz | Fastqsanger.gz | |||
| SRR9090561_1.fastq.gz | Fastqsanger.gz | |||
| SRR9090561_2.fastq.gz | Fastqsanger.gz | |||
| SRR9090562_1.fastq.gz | Fastqsanger.gz |
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Project description:Transcriptome analysis of M07e cells and patient derived AMKL cells upon SEKIT inhibition by CRISPRi
| PRJNA543771 | ENA
Project description:In the recent years, massively parallel sequencing approaches identified hundreds of mutated genes in cancer providing an unprecedented amount of information about mechanisms of cancer cell maintenance and progression. However, while (it is widely accepted that) transformation processes result from oncogenic cooperation between deregulated genes and pathways, the functional characterization of candidate key players is mostly performed at the single gene level which is generally inadequate to identify these oncogene circuitries. In addition, studies aimed at depicting oncogenic cooperation involve the generation of challenging mouse models or the deployment of tedious screening pipelines. Genome wide mapping of epigenomic modifications on histone tails or binding of factors such as MED1 and BRD4 allowed identification of clusters of regulatory elements, also termed Super-Enhancers (SE). Functional annotation of these regions revealed their high relevance during normal tissue development and cancer ontogeny. An interesting paradigm of the tumorigenic function of these SE regions comes from ETO2-GLIS2-driven acute megakaryoblastic leukemia (AMKL) in which the fusion protein ETO2-GLIS2 is sufficient to promote an aberrant transcriptional network by the rewiring of SE regions4. We thus hypothesized that important regulatory regions could control simultaneously expression of genes cooperating in functional modules to promote cancer development. In an effort to identify such modules, we deployed a genome-wide CRISPRi-based screening approach and nominated SE regions that are functionally linked to leukemia maintenance. In particular, we pinpointed a novel SE region regulating the expression of both tyrosine kinases KIT and PDGFRA. Whereas the inhibition of each kinase alone affected modestly cancer cell growth, combined inhibition of both receptors synergizes to impair leukemia cell growth and survival. Our results demonstrate that genome-wide screening of regulatory DNA elements can identify co-regulated genes collaborating to promote cancer and could open new avenues to the concept of combined gene inhibition upon single hit targeting.
2022-03-04 | GSE131458 | GEO
Project description:The goal of this study is to define a gene expression signature unique to DS-AMKL (acute megakaryoblastic leukemia or FAB M7 leukemia). A similar study was done previously, but using unfractionated patient leukemic samples. In this study, we sorted megakaryocytic leukemia blasts from patients and then compared their gene expression signatures to those from similarly sorted blasts from patients with non-DS AMKL. This allowed us to identify a gene expression signature more unique to DS-AMKL samples.
2010-08-01 | GSE16677 | GEO
Project description:In the recent years, massively parallel sequencing approaches identified hundreds of mutated genes in cancer providing an unprecedented amount of information about mechanisms of cancer cell maintenance and progression. However, while (it is widely accepted that) transformation processes result from oncogenic cooperation between deregulated genes and pathways, the functional characterization of candidate key players is mostly performed at the single gene level which is generally inadequate to identify these oncogene circuitries. In addition, studies aimed at depicting oncogenic cooperation involve the generation of challenging mouse models or the deployment of tedious screening pipelines. Genome wide mapping of epigenomic modifications on histone tails or binding of factors such as MED1 and BRD4 allowed identification of clusters of regulatory elements, also termed Super-Enhancers (SE). Functional annotation of these regions revealed their high relevance during normal tissue development and cancer ontogeny. An interesting paradigm of the tumorigenic function of these SE regions comes from ETO2-GLIS2-driven acute megakaryoblastic leukemia (AMKL) in which the fusion protein ETO2-GLIS2 is sufficient to promote an aberrant transcriptional network by the rewiring of SE regions4. We thus hypothesized that important regulatory regions could control simultaneously expression of genes cooperating in functional modules to promote cancer development. In an effort to identify such modules, we deployed a genome-wide CRISPRi-based screening approach and nominated SE regions that are functionally linked to leukemia maintenance. In particular, we pinpointed a novel SE region regulating the expression of both tyrosine kinases KIT and PDGFRA. Whereas the inhibition of each kinase alone affected modestly cancer cell growth, combined inhibition of both receptors synergizes to impair leukemia cell growth and survival. Our results demonstrate that genome-wide screening of regulatory DNA elements can identify co-regulated genes collaborating to promote cancer and could open new avenues to the concept of combined gene inhibition upon single hit targeting.
2022-03-04 | GSE131460 | GEO
Project description:Acute megakaryoblastic leukemia (AMKL) is a subtype of acute myeloid leukemia with clinical heterogeneity. The poor prognosis of AMKL means that new therapies need to be developed to treat this disease. Studies have shown that the dysregulation of alternative splicing is associated with the occurrence and development of AMKL and the increase of chemotherapy resistance. indisulam, as a synthetic aryl sulfonamide, can effectively treat solid tumors by targeting the splicing factor RBM39. However, the effects of indisulam on AMKL and the underlying molecular mechanisms remain to be thoroughly investigated. We first screened AMKL for indisulam susceptibility in a public drug-susceptibility database. The results showed that AMKL was more sensitive to insulin than other tumor types. We then treated human AMKL cell lines (CMK, MEG01 and M07e) with indisulam to evaluate its efficacy and investigate its molecular targets. The results suggest that indisulam induces RBM39 degradation and inhibits tumor growth in a dose-dependent manner. RNA-seq and proteomic analyses revealed that indisulam selectively degraded RBM39 and resulted in mis-splicing of the transcription factor ZMYND8, which maintains AML survival and proliferation. We knocked down ZMYND8 and confirmed the critical role of ZMYND8 in maintaining AMKL survival and proliferation. In addition, we verified that the anti-tumor effect of indisulam on AMKL was DCAF15 dependent. By targeting DCAF15 using CRISPR/Cas9 system, we confirmed the DCAF15-dependent effect of indisulam in both in vivo and in vitro models. Taken together, our study suggests that indisulam has promising therapeutic potential for AMKL by specifically targeting the splicing factor RBM39 and is dependent on the expression of DCAF15. In addition, our study identified ZMYND8 as a novel downstream regulator of RBM39 and the RBM39-ZMYND8 axis is important for AMKL survival and proliferation.
2025-04-23 | GSE266925 | GEO
Project description:The goal of this study is to define a gene expression signature unique to DS-AMKL (acute megakaryoblastic leukemia or FAB M7 leukemia). A similar study was done previously, but using unfractionated patient leukemic samples. In this study, we sorted megakaryocytic leukemia blasts from patients and then compared their gene expression signatures to those from similarly sorted blasts from patients with non-DS AMKL. This allowed us to identify a gene expression signature more unique to DS-AMKL samples. The leukemic blasts were sorted based on CD41, CD7, CD117, CD33, and CD34 antibodies as previously described (Klin. Padiatr. 217, 126-134).
2010-08-01 | E-GEOD-16677 | biostudies-arrayexpress
Project description:To test whether the activity of PIM proteins promotes an aberrant activation of the molecular cascades that are essential for the leukemogenic effects mediated by JAK/STAT pathway mutations, we analyzed RNA-seq data from M07e cells expressing JAK3Q988P that were treated with PIM447 or left untreated.
2024-07-15 | GSE266986 | GEO
Project description:Acute megakaryoblastic leukemia (AMKL) is a heterogeneous disease generally associated with poor prognosis. Gene expression profiles indicate the existence of distinct molecular subgroups, and several genetic alterations have been characterized in the past years, including the t(1;22)(p13;q13) and the trisomy 21 associated with GATA1 mutations. However, the majority of patients do not present known mutations, and the limited access to primary patient leukemic cells impedes the efficient development of novel therapeutic strategies. In this study, using a xenotransplantation approach, we have modeled human pediatric AMKL in immunodeficient mice. Analysis of high-throughput RNA sequencing identified recurrent fusion genes defining new molecular subgroups.
2016-05-21 | E-MTAB-4697 | biostudies-arrayexpress
Project description:In the previous studies, we reported that Mpl alternative splicing form Mpl-del overexpressed in acute megakaryoblasttic leukemia (AMKL) patients and mediated thrombopoietin signaling to promote AMKL cells malignant proliferation and chemotherapy resisitance. To investigate the detailed mechanism of Mpl-del mediated AMKL cells proliferation and survival, the AMKL cell Dami stably expressing GFP or Mpl-del-GFP were established by transduction with GFP or Mpl-del-GFP lentiviruses and treated with 20ng/ml TPO for RNA-SEQ analysis to examine the expression of proliferation and survival-related genes. Our results indicated that the levels of the "leading edge" genes that account for survival and prolieration were significantly higher in Mpl--del overexpressed AMKL cells.
2019-04-04 | GSE127762 | GEO
Project description:In the previous studies, we reported that c-Mpl alternative splicing form c-Mpl-del overexpressed in acute megakaryoblasttic leukemia (AMKL) patients and mediated thrombopoietin signaling to promote AMKL cells malignant proliferation and chemotherapy resisitance. To investigate the detailed mechanism of c-Mpl-del mediated AMKL cells survival and chemotherapy resisitance, the AMKL cell Dami stably expressing GFP, c-Mpl-del-GFP or c-Mpl-p-GFP were established by transduction with GFP, c-Mpl-del-GFP or c-Mpl-p-GFP lentiviruses and treated with or without Ara-c (10μM) in the presence of 20ng/mL TPO for RNA-SEQ analysis to exame the expression of survival-related genes. Our results indicate that the levels of the "leading edge" genes that account for survival and prolieration are significantly higher in c-Mpl-del overexpressed AMKL cells. Meanwhile, the expression of c-Mpl-del promotes the tolerance of AMKL cells to Ara-c.
2020-02-27 | GSE145949 | GEO