ChIP-seq analysis of H3K27ac, TLX3 and MYB in human primary leukemia cells and cell lines
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA821194 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18518500.fastq.gz | Fastqsanger.gz | |||
| SRR18518501.fastq.gz | Fastqsanger.gz | |||
| SRR18518502.fastq.gz | Fastqsanger.gz | |||
| SRR18518503.fastq.gz | Fastqsanger.gz | |||
| SRR18518492.fastq.gz | Fastqsanger.gz |
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Project description:Structural variants (SVs) involving enhancer hijacking can disrupt chromatin topologies to cause oncogene activation in cancer genomes, yet the molecular determinants for the transcriptional output of enhancer hijacking remain largely unknown. We developed a multimodal approach to integrate genome sequencing, chromosome conformation, and sequence-based deep learning for quantitative analysis of transcriptional effects and structural reorganization imposed by SVs in leukemic genomes. We identified candidate pathogenic SVs including recurrent t(5;14) translocations that cause the hijacking of BCL11B enhancers for oncogenic activation of TLX3-dependent transcriptional programs. By engineering patient-associated t(5;14) in isogenic leukemia cells, we uncovered an uncharacterized mechanism whereby DNA methylation serves as an epigenetic barrier to enhancer hijacking and loss of epigenetic barrier is a molecular determinant for the transcriptional output of pathogenic SVs. Hence, leveraging the epigenetic barriers of SV-mediated oncogenic programs may provide new opportunities to reprogram gene regulation as epigenetic therapies in human disease.
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Project description:Peptidomimetic blockade of MYB in acute myeloid leukemia [H3K27ac ChIP-seq]
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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.
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Project description:The transcription factor c-Myb a key regulator in proliferation and differentiation of hematopoietic progenitor cells, is precisely regulated during essential cellular processes. Overexpression and rearrangement of c-myb has been reported in human tumors including myeloid leukemia, but exact regulatory mechanisms have remained elusive. Here, we identified, using 4C assay with the c-myb promoter as an anchor, the interaction site at -34k region upstream of c-myb gene that are involved in c-myb expression. Furthermore, we found that the long-range interactions changed with c-myb being down-regulated on differentiation progress in human myeloid leukemia cell lines. Taken together, our date revealed that a potential c-myb enhancer-promoter interactions may be a particularly important regulatory mechanism for c-myb gene expression in human myeloid leukemia cells.
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Project description:Structural variants (SVs) involving enhancer hijacking can disrupt chromatin topologies to cause oncogene activation in cancer genomes, yet the molecular determinants for the transcriptional output of enhancer hijacking remain largely unknown. We developed a multimodal approach to integrate genome sequencing, chromosome conformation, and sequence-based deep learning for quantitative analysis of transcriptional effects and structural reorganization imposed by SVs in leukemic genomes. We identified candidate pathogenic SVs including recurrent t(5;14) translocations that cause the hijacking of BCL11B enhancers for oncogenic activation of TLX3-dependent transcriptional programs. By engineering patient-associated t(5;14) in isogenic leukemia cells, we uncovered an uncharacterized mechanism whereby DNA methylation serves as an epigenetic barrier to enhancer hijacking and loss of epigenetic barrier is a molecular determinant for the transcriptional output of pathogenic SVs. Hence, leveraging the epigenetic barriers of SV-mediated oncogenic programs may provide new opportunities to reprogram gene regulation as epigenetic therapies in human disease.
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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:It is now well established that members of the homeobox gene family play a critical role in normal hematopoietic cell development and that their unbalanced or ectopic expression can lead to characteristic perturbations in haemopoiesis and the onset of leukaemia. TLX3 expression in human haematologic malignancies is exclusive to T-ALL, where it is almost universally associated with transformation of early cortical CD4+CD8+ DP thymocytes. investigated the impact of ectopic TLX3 expression on T cell development, and the initiating mechanisms of T-cell transformation leading to leukemia onset. Forced expression of TLX3 disrupted the thymic develoment at DN-like stage giving rise to immortalized preleukemic clones.
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Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological disease originating from the malignant transformation of T-cell progenitors caused by the accumulation of genetic aberrations. One fifth of T-ALL patients are characterized by the ectopic expression of the homeobox transcription factor TLX3, which is normally not expressed in hematopoietic cells. Strikingly, this TLX3 positive subgroup of T-ALL has a high frequency of FLT3 mutations. Co-expression of TLX3 and FLT3-ITD in ex vivo pro-T cells conferred IL7 independent growth, confirming that TLX3 expression and FLT3 signaling cooperate to transform T-cells and make them less dependent on extracellular signals. After inducing TLX3 expression for 24 hours in Pro-T cells, transducin-like enhancer of split 4 (Tle4) was detected to be downregulated. Interestingly, T-ALL patients also present a strongly decreased expression of TLE4 specific to TLX3 and TLX1 subtypes. Family members of the transcriptional corepressor TLE4 have been described to interact and thus, inhibit transcription factors, through their interaction with an Engrailed-homology 1 (Eh1) domain. Generation of a point mutation in the Eh1 domain present at the N-terminus of TLX3 allowed us to show that TLE4 has a repressive effect on TLX3 activity. Together, we propose a TLX3+FLT3-ITD Pro-T cell model and use this to illustrate that low expression levels of TLE4 are favourable for the oncogenic function of TLX3.
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Project description:Transcriptome analysis of two Ph+ acute lymphoblastic leukemia cell lines after doxycycline induced silencing of MYB. Current treatment options for Ph+ acute lymphoblastic leukemia (ALL) do not result in long term remission. MYB transcription factor has been shown to be selectively important for Ph+ ALL cell survival and proliferation however the mechanisms for this oncogene addiction are poorly understood and no bona-fide MYB inhibitors currently exist. To overcome these limitations, we analyzed the transcriptome of MYB silenced Ph+ ALL in search for genes regulated by MYB that could serve as potential pharmacological targets. We observed that among MYB-regulated genes, those involved in cell cycle regulation are significantly over-represented. We found that CDK6 and BCL2 are MYB targets pivotal for MYB dependent regulation of proliferation and survival respectively. Furthermore, their inhibition suppresses leukemia growth in vitro and in vivo thus providing a potential treatment approach for patients that fails or do not respond to conventional treatments.
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Project description:ChIP-Seq to study the binding of TLX3 in the mouse cell line DN-TLX3
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