Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA203263 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR851826.fastq.gz | Fastqsanger.gz | |||
| SRR851827.fastq.gz | Fastqsanger.gz | |||
| SRR851828.fastq.gz | Fastqsanger.gz | |||
| SRR851829.fastq.gz | Fastqsanger.gz | |||
| SRR851830.fastq.gz | Fastqsanger.gz |
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Project description:FOXM1 Controls Leukemia Stem Cell Fate in MLL-Rearranged AML
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Project description:Cell of origin determines clinically relevant subtypes of MLL-rearranged AML
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Project description:Members of the TALE (Three-amino acid loop extension) family of atypical homeodomain-containing transcription factors are prominent downstream effectors of oncogenic fusion proteins generated from translocations involving the mixed lineage leukemia (MLL) gene. A particular well-characterized member of this protein family is MEIS1, which together with HOXA proteins, orchestrates a transcriptional program required for the maintenance of MLL-rearranged acute myeloid leukemia (AML). Although TALE family proteins are mainly described as transcriptional activators TGIF1 (TGF-β induced factor) / TGIF2 are considered as transcriptional repressors. However, as their function in MLL-rearranged AML is largely unknown, we tested the potential importance of TGIF1 in the maintenance of MLL-rearranged AML. We find that expression of TGIF1 in MLL-AF9 transformed cells (MAF9) leads to cell cycle exit and differentiation in vitro and delayed leukemic onset in vivo. In accordance, MLL-rearranged patient blasts display lower levels of TGIF1 and TGIF1 expression in general correlates positively with survival. Mechanistically, we show that TGIF1 interferes with a MEIS1-dependent transcriptional program by associating to MEIS1-bound region in a competitive manner. Collectively, these findings demonstrate that TALE family members can act both positively and negatively on transcriptional programs responsible for the maintenance of MLL-rearranged AML.
2014-11-11 | GSE55287 | GEO
Project description:ZNF521 is a multiple zinc finger transcription factor previously identified because abundantly and selectively expressed in normal CD34+ hematopoietic stem and progenitor cells. From microarray datasets, aberrant expression of ZNF521 has been reported in both pediatric and adult acute myeloid leukemia (AML) patients with MLL gene rearrangements. However, a proper validation of microarray data is lacking, likewise ZNF521 contribution in MLL-rearranged AML is still uncertain. In this study, we show that ZNF521 is significantly upregulated in MLL translocated AML patients from a large pediatric cohort, regardless of the type of MLL translocations such as MLL-AF9, MLL-ENL, MLL-AF10 and MLL-AF6 fusion genes. Our in vitro functional studies demonstrate that ZNF521 play a critical role in the maintenance of the undifferentiated state of MLL-rearranged cells. Furthermore, analysis of the ZNF521 gene promoter region shows that ZNF521 is a direct downstream target of both MLL-AF9 and MLL-ENL fusion proteins. Gene expression profiling of MLL-AF9-rearranged THP-1 cells after depletion of ZNF521 reveals correlation with several expression signatures including stem cell-like and MLL fusion dependent programs. These data suggest that MLL fusion proteins activate ZNF521 expression to maintain the undifferentiated state and contribute to leukemogenesis. ZNF521 is required to block differentiation in MLL-rearranged AML cells
2017-03-31 | GSE79110 | GEO
Project description:MLL-rearranged acute myeloid leukemia (AML) remains a fatal disease with a high rate of relapse and therapeutic failure due to chemotherapy resistance. In analysis of our Affymetrix microarray profiling of human AML and normal control samples, we found that ALOX5 is especially down-regulated in MLL-rearranged AML. Our colony forming/replating and bone marrow transplantation (BMT) assays showed that Alox5 exhibited a moderate anti-tumor effect both in vitro and in vivo. Strikingly, leukemic cells with Alox5 overexpression showed a significantly higher sensitivity to the standard chemotherapeutic agents, i.e., doxorubicin (DOX) and cytarabine (Ara-C). The drug-sensitizing role of Alox5 was further confirmed in human and murine MLL-rearranged AML cell models in vitro, as well as in the in vivo MLL-rearranged AML BMT model coupled with treatment of “5+3” (i.e. DOX plus Ara-C) regimen. Our RNA-seq analysis showed that Stat and K-Ras signaling pathways were negatively correlated with Alox5 overexpression in MLL-AF9-leukemic blast cells, implying targeting those pathways likely contributes to Alox5’s functions. Collectively, our work shows that ALOX5 plays a moderate anti-tumor role and functions as a drug sensitizer, with a therapeutic potential, in MLL-rearranged AML.
2017-06-09 | GSE94840 | GEO
Project description:Aberrant gene expression is a hallmark of acute leukemias. However, therapeutic strategies for its blockade are generally lacking, in large part due to the pharmacologic challenges of drugging transcription factors. MYB-driven gene trans-activation with CREB-binding protein (CBP) is required for the initiation and maintenance of a variety of acute lymphoblastic and myeloid leukemias, including refractory MLL-rearranged leukemias. Using structure-guided molecular design, we developed a prototypical peptidomimetic inhibitor MYBMIM that interferes with the assembly of the molecular MYB:CBP complex at ¼M concentrations and rapidly accumulates in the nuclei of AML cells. We found that treatment of AML cells with MYBMIM, but not with its inactive near-isosteric analogue TG3, led to the displacement and dissociation of MYB:CBP complex in cells, displacement of MYB from oncogenic enhancers and promoters enriched for MYB binding sites, and rapid downregulation of MYB-dependent gene expression, including of MYC and BCL2 oncogenes. Both human MLL-rearranged and non-rearranged AML cells, but not normal CD34+ umbilical cord blood progenitor cells, underwent sustained mitochondrial apoptosis in response to MYBMIM treatment, an effect that could be partially rescued by ectopic expression of BCL2. We observed that MYBMIM treatment impeded leukemia growth and extended survival of immunodeficient mice engrafted with primary patient-derived MLL-rearranged leukemia cells. These findings emphasize the exquisite dependence of human AML on MYB:CBP transcriptional dysregulation, and establish a pharmacologic approach for its therapeutic blockade.
2018-02-23 | GSE94240 | GEO
Project description:Aberrant gene expression is a hallmark of acute leukemias. However, therapeutic strategies for its blockade are generally lacking, in large part due to the pharmacologic challenges of drugging transcription factors. MYB-driven gene trans-activation with CREB-binding protein (CBP) is required for the initiation and maintenance of a variety of acute lymphoblastic and myeloid leukemias, including refractory MLL-rearranged leukemias. Using structure-guided molecular design, we developed a prototypical peptidomimetic inhibitor MYBMIM that interferes with the assembly of the molecular MYB:CBP complex at ¼M concentrations and rapidly accumulates in the nuclei of AML cells. We found that treatment of AML cells with MYBMIM, but not with its inactive near-isosteric analogue TG3, led to the displacement and dissociation of MYB:CBP complex in cells, displacement of MYB from oncogenic enhancers and promoters enriched for MYB binding sites, and rapid downregulation of MYB-dependent gene expression, including of MYC and BCL2 oncogenes. Both human MLL-rearranged and non-rearranged AML cells, but not normal CD34+ umbilical cord blood progenitor cells, underwent sustained mitochondrial apoptosis in response to MYBMIM treatment, an effect that could be partially rescued by ectopic expression of BCL2. We observed that MYBMIM treatment impeded leukemia growth and extended survival of immunodeficient mice engrafted with primary patient-derived MLL-rearranged leukemia cells. These findings emphasize the exquisite dependence of human AML on MYB:CBP transcriptional dysregulation, and establish a pharmacologic approach for its therapeutic blockade.
2018-02-23 | GSE107078 | GEO
Project description:Acute myeloid leukemia (AML) carrying MLL rearrangements. We applied WGBS and the informME analysis pipeline to investigate the role of DNA methylation stochasticity in MLL-rearranged AML.
2020-03-02 | GSE135869 | GEO
Project description:Leukemias that harbor translocations involving the mixed lineage leukemia gene (MLL) possess unique biological characteristics and often have an unfavorable prognosis. Gene expression analyses demonstrate a distinct profile for MLL-rearranged leukemias with consistent high-level expression of select Homeobox genes including HOXA9. Here, we investigated the effects of HOXA9 suppression in MLL-rearranged and MLL-germline leukemias utilizing RNAi. Gene expression profiling after HOXA9 suppression demonstrated co-downregulation of a program highly expressed in human MLL-AML (this study) and murine MLL-leukemia (Krivtsov et al. 2006) stem cells including HOXA10, MEIS1, PBX3 and MEF2C. Our data indicates an important role for HOXA9 in human MLL-rearranged leukemias, and suggests targeting HOXA9 or downstream programs may be a novel therapeutic option. Experiment Overall Design: RNA was purified from t(9;11) MOLM-14 AML cells 44h after transduction in triplicates with 2 of the two most effective HOXA9shRNA constructs (3 x 1F3-HOXA9shRNA; 3 x 2A5-HOXA9shRNA) or GFP-controlshRNA (6x).
2009-01-26 | E-GEOD-13714 | biostudies-arrayexpress
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. Primary KSL, CMP, and GMP cells from wildtype controls and C/Ebpa knockouts were used for RNA extraction and hybridization on Affymetrix microarrays. We also compared the microarray samples of leukemic granulocyte macrophage progenitor compartments (L-GMPs) from MLL-AF9 transformed control or cytokine rescued C/EBPa KO leukemic mouse bone marrow and their secondary recipients with those non-Leukemia KSLs and CMPs from MLL-AF9 transduecd KO recipients with no leukemia development.
2015-08-04 | E-GEOD-71687 | biostudies-arrayexpress