Transcription Factor MEF2D is Required for the Maintenance of MLL-rearranged Acute Myeloid Leukemia
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ABSTRACT:
PROVIDER: PRJNA698831 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13610626_1.fastq.gz | Fastqsanger.gz | |||
| SRR13610626_2.fastq.gz | Fastqsanger.gz | |||
| SRR13610627_1.fastq.gz | Fastqsanger.gz | |||
| SRR13610627_2.fastq.gz | Fastqsanger.gz | |||
| SRR13610628_1.fastq.gz | Fastqsanger.gz |
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Project description:Acute myeloid leukemia (AML) with MLL-rearrangement (MLL-r) comprises approximately 10% of all AML cases and portends poor outcomes. Much remains to be uncovered on how MLL-r AML drives leukemia development while preventing cells from normal myeloid differentiation. Here, we identified that transcription factor MEF2D is a highly expressed gene with a super-enhancer MLL-r AML. Knockout of MEF2D profoundly impaired leukemia growth, induced myeloid differentiation, and delayed oncogenic progression in vivo. Mechanistically, MEF2D loss led to robust activation of a CEBPE-centered myeloid differentiation program in AML cells. Chromatin profiling revealed that MEF2D binds to and suppresses the chromatin accessibility of CEBPE cis-regulatory regions. In human acute leukemia patient samples, MEF2D expression showed a strong negative correlation with the expression of CEBPE. Depletion of CEBPE partially rescued the cell growth defect and myeloid cell differentiation induced by the loss of MEF2D. Lastly, we show that MEF2D is positively regulated by HOXA9, and downregulation of MEF2D is an important mechanism for DOT1L inhibitor-induced anti-leukemia effects in MLL-r AML. Collectively, our findings suggest that MEF2D plays a critical role in human MLL-r AML and uncover the MEF2D-CEBPE axis as a crucial transcriptional mechanism regulating leukemia cell self-renewal and differentiation block in MLL-r AML.
2021-10-03 | GSE165981 | GEO
Project description:Acute myeloid leukemia (AML) with MLL-rearrangement (MLL-r) comprises approximately 10% of all AML cases and portends poor outcomes. Much remains to be uncovered on how MLL-r AML drives leukemia development while preventing cells from normal myeloid differentiation. Here, we identified that transcription factor MEF2D is a highly expressed gene with a super-enhancer MLL-r AML. Knockout of MEF2D profoundly impaired leukemia growth, induced myeloid differentiation, and delayed oncogenic progression in vivo. Mechanistically, MEF2D loss led to robust activation of a CEBPE-centered myeloid differentiation program in AML cells. Chromatin profiling revealed that MEF2D binds to and suppresses the chromatin accessibility of CEBPE cis-regulatory regions. In human acute leukemia patient samples, MEF2D expression showed a strong negative correlation with the expression of CEBPE. Depletion of CEBPE partially rescued the cell growth defect and myeloid cell differentiation induced by the loss of MEF2D. Lastly, we show that MEF2D is positively regulated by HOXA9, and downregulation of MEF2D is an important mechanism for DOT1L inhibitor-induced anti-leukemia effects in MLL-r AML. Collectively, our findings suggest that MEF2D plays a critical role in human MLL-r AML and uncover the MEF2D-CEBPE axis as a crucial transcriptional mechanism regulating leukemia cell self-renewal and differentiation block in MLL-r AML.
2021-10-02 | GSE165980 | GEO
Project description:Acute myeloid leukemia (AML) with MLL-rearrangement (MLL-r) comprises approximately 10% of all AML cases and portends poor outcomes. Much remains to be uncovered on how MLL-r AML drives leukemia development while preventing cells from normal myeloid differentiation. Here, we identified that transcription factor MEF2D is a highly expressed gene with a super-enhancer MLL-r AML. Knockout of MEF2D profoundly impaired leukemia growth, induced myeloid differentiation, and delayed oncogenic progression in vivo. Mechanistically, MEF2D loss led to robust activation of a CEBPE-centered myeloid differentiation program in AML cells. Chromatin profiling revealed that MEF2D binds to and suppresses the chromatin accessibility of CEBPE cis-regulatory regions. In human acute leukemia patient samples, MEF2D expression showed a strong negative correlation with the expression of CEBPE. Depletion of CEBPE partially rescued the cell growth defect and myeloid cell differentiation induced by the loss of MEF2D. Lastly, we show that MEF2D is positively regulated by HOXA9, and downregulation of MEF2D is an important mechanism for DOT1L inhibitor-induced anti-leukemia effects in MLL-r AML. Collectively, our findings suggest that MEF2D plays a critical role in human MLL-r AML and uncover the MEF2D-CEBPE axis as a crucial transcriptional mechanism regulating leukemia cell self-renewal and differentiation block in MLL-r AML.
2021-10-02 | GSE165979 | GEO
Project description:Transcription Factor MEF2D is Required for the Maintenance of MLL-rearranged Acute Myeloid Leukemia [ChIP-Seq]
| PRJNA698822 | ENA
Project description:Transcription Factor MEF2D is Required for the Maintenance of MLL-rearranged Acute Myeloid Leukemia [RNA-Seq]
| PRJNA698823 | ENA
Project description:Transcription Factor MEF2D is Required for the Maintenance of MLL-rearranged Acute Myeloid Leukemia [ATAC-Seq]
| PRJNA698821 | ENA
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:The aim of the study was to investigate the role of TGIF1 in MLL-AF9 transformed cells 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 | GSE55713 | 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:Acute myeloid leukemia (AML) with MLL-rearrangement (MLL-r) comprises ∼10% of all AML cases and portends poor outcomes. Much remains uncovered on how MLL-r AML drives leukemia development while preventing cells from normal myeloid differentiation. Here, we identified that transcription factor MEF2D is a super-enhancer-associated, highly expressed gene in MLL-r AML. Knockout of MEF2D profoundly impaired leukemia growth, induced myeloid differentiation, and delayed oncogenic progression in vivo. Mechanistically, MEF2D loss led to robust activation of a CEBPE-centered myeloid differentiation program in AML cells. Chromatin profiling revealed that MEF2D binds to and suppresses the chromatin accessibility of CEBPE cis-regulatory regions. In human acute leukemia samples, MEF2D expression showed a strong negative correlation with the expression of CEBPE. Depletion of CEBPE partially rescued the cell growth defect and myeloid cell differentiation induced by the loss of MEF2D. Lastly, we show that MEF2D is positively regulated by HOXA9, and downregulation of MEF2D is an important mechanism for DOT1L inhibitor-induced antileukemia effects. Collectively, our findings suggest that MEF2D plays a critical role in human MLL-r AML and uncover the MEF2D-CEBPE axis as a crucial transcriptional mechanism regulating leukemia cell self-renewal and differentiation block.
| S-EPMC8759131 | biostudies-literature