HOXA9 Reprograms the Enhancer Landscape During Leukemic Transformation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA401435 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6003920.fastq.gz | Fastqsanger.gz | |||
| SRR6003930.fastq.gz | Fastqsanger.gz | |||
| SRR6003940.fastq.gz | Fastqsanger.gz | |||
| SRR6003921.fastq.gz | Fastqsanger.gz | |||
| SRR6003931.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:This SuperSeries is composed of the SubSeries listed below.
2018-09-05 | GSE103508 | GEO
Project description:Aberrant expression of HOXA9 is a prominent feature of acute leukemia driven by diverse oncogenes. Here we show that HOXA9 overexpression in myeloid and B progenitor cells leads to significant enhancer reorganizations with prominent emergence of leukemia-specific de novo enhancers. Alterations in the enhancer landscape lead to activation of an ectopic embryonic gene program. We show that HOXA9 functions as a pioneer factor at de novo enhancers and recruits CEBP? and the MLL3/MLL4 complex. Genetic deletion of MLL3/MLL4 blocks histone H3K4 methylation at de novo enhancers and inhibits HOXA9/MEIS1-mediated leukemogenesis in vivo. These results suggest that therapeutic targeting of HOXA9-dependent enhancer reorganization can be an effective therapeutic strategy in acute leukemia with HOXA9 overexpression.
| S-EPMC6179449 | biostudies-literature
Project description:Aberrant expression of homeobox transcription factor HOXA9 is a central component of the leukemogenic program driven by diverse oncogenes. Here we show that HOXA9 overexpression in myeloid progenitor cells and pro-B cells leads to significant rearrangement of the epigenetic landscape with prominent emergence of cancer specific de novo enhancers. HOXA9 acts as a pioneer factor at the de novo enhancers and is required for recruitment of transcription factor CEBP/a and the histone H3K4 methyltransferase MLL3/MLL4 complex. HOXA9 function at the de novo enhancer is distinct from its physiological role at distal enhancers during normal hematopoietic development. Genetic deletion of MLL3/4 specifically affects the active enhancer signatures at de novo enhancers and inhibits HOXA9/MEIS1-mediated leukemogenesis. Our study reveals a previously uncharacterized role of HOXA9 and the MLL3/4 complex in leukemogenesis and provide mechanistic insights in epigenetic deregulation during malignant transformation.
2018-09-05 | GSE103447 | GEO
Project description:Aberrant expression of homeobox transcription factor HOXA9 is a central component of the leukemogenic program driven by diverse oncogenes. Here we show that HOXA9 overexpression in myeloid progenitor cells and pro-B cells leads to significant rearrangement of the epigenetic landscape with prominent emergence of cancer specific de novo enhancers. HOXA9 acts as a pioneer factor at the de novo enhancers and is required for recruitment of transcription factor CEBP/a and the histone H3K4 methyltransferase MLL3/MLL4 complex. HOXA9 function at the de novo enhancer is distinct from its physiological role at distal enhancers during normal hematopoietic development. Genetic deletion of MLL3/4 specifically affects the active enhancer signatures at de novo enhancers and inhibits HOXA9/MEIS1-mediated leukemogenesis. Our study reveals a previously uncharacterized role of HOXA9 and the MLL3/4 complex in leukemogenesis and provide mechanistic insights in epigenetic deregulation during malignant transformation.
2018-09-05 | GSE103448 | GEO
Project description:C-terminal mutation of Nucleophosmin 1 (NPM1C+) was thought to be a primary driving event that reprograms leukemic-associated transcription program to transform hematopoietic stem and progenitor cells (HS/PCs). However, molecular mechanism underlying NPM1C+-driven leukemogenesis remain elusive. Here, we reported that NPM1C+ reprograms MIZ-1/MYC regulatory axis by altering NPM1-associated CTCF-driven topologically associated domains (TADs) that switched the balance of MIZ1 interaction with co-repressors MYC/G9A and coactivator p300 to control cell cycle progress and myeloid lineage-specific PU.1/CEBPa transcription networks. These alterations impaired hematopoietic cell cycle progression and myeloid differentiation. Knock-in of NPM1C+ in bone marrow HSPCs alters cell cycle regulators and myeloid master transcription factor (TF) TAD topology, chromatin accessibility, and gene regulation leading blockage of myeloid differentiation. Retention of NPM1 or reactivation of PU.1 or CEBPa within nucleus activates differentiation program by reorganizing TADs critical for myeloid TFs and cell cycle regulator, leading to blockage of NPM1C+-driven leukemogenesis. Thus, our data revealed that NPM1C+ reshapes CTCF-defined TAD topology to reprogram signature leukemic transcription program require for cell cycle progression and leukemic progression. Restoration of myeloid transcription program in nucleus reversed NPM1C+-driven transcription signature and promotes myeloid differentiation leading to mitigation of AML.
2023-08-09 | GSE208022 | GEO
Project description:To study the oncogenic mechanism triggered by the leukemic fusion protein NUP98-HOXA9, we cloned the cDNA of NUP98-HOXA9 into a retroviral vector (pMSCV-IRES-GFP) and efficiently transduced the HEK293FT human cell line. We performed a ChIP-seq analysis to identify the DNA binding sites of NUP98-HOXA9. These results allowed us to demonstrate that NUP98-HOXA9 regulates the expression of genes involved in the development of Acute Myeloid Leukemia by directly interacting with their enhancer regions. We further investigated the functional contribution to the DNA binding profile of the two moieties that compose the fusion protein. We cloned the coding region of HOXA9 wt and NUP98 wt in the same retroviral vector, established two new cellular models, 293FT-HOXA9 and 293FT-NUP98, and performed separate ChIP-seq analyses. We demonstrated that both moieties contribute importantly to the regulation of the target genes.
2016-12-31 | GSE62586 | GEO
Project description:Accumulating evidence indicates that HOXA9 dysregulation is sufficient and necessary for leukemic transformation. Leukemia subtypes showing HOXA9 overexpression include those carrying MLL gene rearrangements (MLL-r), NPM1c mutations, and other genetic alterations. HOXA9 protein is a poor therapeutic target as it lacks targetable pocket domains. Therefore, understanding HOXA9’s functional downstream genes and its regulation might provide alternative therapeutic targets. However, it remains largely unknown how HOXA9, as a homeobox transcriptional factor, binds to noncoding regulatory sequences and controls the downstream genes in MLL-r leukemia and across leukemias of other genetic subtypes. In this study, we have successfully conducted dropout CRISPR screens in the MLL-r SEM cell line stably expressing Cas9 against ~1,800 HOXA9 binding peaks. Integrative data analysis identified six reproducible noncoding hits, including a positive control located in the distal enhancer of FLT3. Cas9-editing and dCas9-KRAB silencing HOXA9’s binding site in distal region of FLT3 reduced transcription and impaired cell proliferation in vitro and in vivo. In addition, RNA-seq and Q-PCR analysis further identified the functional relevant downstream genes upon CRISPR editing of other candidate HOXA9-bound noncoding segments, including survival essential genes as XBP1, JUN and BAHCC1. In summary, the work is significant as it will advance our understanding of how HOXA9-associated transcription programs reconstruct the regulatory network specifying MLL-r dependency. Moreover, our study will promote the future development of HOXA9-mediated noncoding regulation, and alternative therapeutic targets in HOXA9-driven (including HOXA9 and possibly NUP98-HOXA9 subtype) leukemia in patients.
2023-10-10 | GSE215926 | GEO
Project description:Characterization of gene expression changes 72 hours after withdrawal of tamoxifen in murine hematopoietic progenitors transformed by Hoxa9-ER/Meis1 using RNAseq. In the presence of tamoxifen (4OHT), Hoxa9-ER localizes to the nucleus of cells allowing for transformation, while withdrawal of 4OHT (culture in EtOH) leads to loss of nuclear Hoxa9-ER. Loss of Hoxa9-ER leads to a decrease in cellular proliferation and differentiation along the myeloid lineage.
2014-06-11 | GSE58359 | GEO
Project description:Accumulating evidence indicates that HOXA9 dysregulation is sufficient and necessary for leukemic transformation. Leukemia subtypes showing HOXA9 overexpression include those carrying MLL gene rearrangements (MLL-r), NPM1c mutations, and other genetic alterations. HOXA9 protein is a poor therapeutic target as it lacks targetable pocket domains. Therefore, understanding HOXA9’s functional downstream genes and its regulation might provide alternative therapeutic targets. However, it remains largely unknown how HOXA9, as a homeobox transcriptional factor, binds to noncoding regulatory sequences and controls the downstream genes in MLL-r leukemia and across leukemias of other genetic subtypes. In this study, we have successfully conducted dropout CRISPR screens in the MLL-r SEM cell line stably expressing Cas9 against ~1,800 HOXA9 binding peaks. Integrative data analysis identified six reproducible noncoding hits, including a positive control located in the distal enhancer of FLT3. Cas9-editing and dCas9-KRAB silencing HOXA9’s binding site in distal region of FLT3 reduced transcription and impaired cell proliferation in vitro and in vivo. In addition, RNA-seq and Q-PCR analysis further identified the functional relevant downstream genes upon CRISPR editing of other candidate HOXA9-bound noncoding segments, including survival essential genes as XBP1, JUN and BAHCC1. In summary, the work is significant as it will advance our understanding of how HOXA9-associated transcription programs reconstruct the regulatory network specifying MLL-r dependency. Moreover, our study will promote the future development of HOXA9-mediated noncoding regulation, and alternative therapeutic targets in HOXA9-driven (including HOXA9 and possibly NUP98-HOXA9 subtype) leukemia in patients.
2023-10-10 | GSE216031 | GEO
Project description:Accumulating evidence indicates that HOXA9 dysregulation is sufficient and necessary for leukemic transformation. Leukemia subtypes showing HOXA9 overexpression include those carrying MLL gene rearrangements (MLL-r), NPM1c mutations, and other genetic alterations. HOXA9 protein is a poor therapeutic target as it lacks targetable pocket domains. Therefore, understanding HOXA9’s functional downstream genes and its regulation might provide alternative therapeutic targets. However, it remains largely unknown how HOXA9, as a homeobox transcriptional factor, binds to noncoding regulatory sequences and controls the downstream genes in MLL-r leukemia and across leukemias of other genetic subtypes. In this study, we have successfully conducted dropout CRISPR screens in the MLL-r SEM cell line stably expressing Cas9 against ~1,800 HOXA9 binding peaks. Integrative data analysis identified six reproducible noncoding hits, including a positive control located in the distal enhancer of FLT3. Cas9-editing and dCas9-KRAB silencing HOXA9’s binding site in distal region of FLT3 reduced transcription and impaired cell proliferation in vitro and in vivo. In addition, RNA-seq and Q-PCR analysis further identified the functional relevant downstream genes upon CRISPR editing of other candidate HOXA9-bound noncoding segments, including survival essential genes as XBP1, JUN and BAHCC1. In summary, the work is significant as it will advance our understanding of how HOXA9-associated transcription programs reconstruct the regulatory network specifying MLL-r dependency. Moreover, our study will promote the future development of HOXA9-mediated noncoding regulation, and alternative therapeutic targets in HOXA9-driven (including HOXA9 and possibly NUP98-HOXA9 subtype) leukemia in patients.
2023-10-10 | GSE216017 | GEO