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Identification of therapeutic targets of the hijacked super-enhancer complex in EVI1-rearranged leukemia

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE153307 | GEO | 2021/04/27

REPOSITORIES: GEO

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Identification of therapeutic targets of the hijacked super-enhancer complex in EVI1-rearranged leukemia.

Project description:Deregulation of the EVI1 proto-oncogene by the GATA2 distal hematopoietic enhancer (G2DHE) is a key event in high-risk acute myeloid leukemia carrying 3q21q26 aberrations (3q-AML). Upon chromosomal rearrangement, G2DHE acquires characteristics of a super-enhancer and causes overexpression of EVI1 at 3q26.2. However, the transcription factor (TF) complex of G2DHE remains poorly characterized. The aim of this study was to unravel key components of G2DHE-bound TFs involved in the deregulation of EVI1. We have identified several CEBPA and RUNX1 binding sites to be enriched and critical for G2DHE function in 3q-AML cells. Using ChIP-SICAP (ChIP followed by selective isolation of chromatin-associated proteins), a panel of chromatin interactors of RUNX1 and CEBPA were detected in 3q-AML, including PARP1 and IKZF1. PARP1 inhibition (PARPi) caused a reduction of EVI1 expression and a decrease in EVI1-G2DHE interaction frequency, highlighting the involvement of PARP1 in oncogenic super-enhancer formation. Furthermore, 3q-AML cells were highly sensitive to PARPi and displayed morphological changes with higher rates of differentiation and apoptosis as well as depletion of CD34 + cells. In summary, integrative analysis of the 3q-AML super-enhancer complex identified CEBPA and RUNX1 associated proteins and nominated PARP1 as a potential new therapeutic target in EVI1 + 3q-AML.

| S-EPMC8550965 | biostudies-literature

Identification of therapeutic targets of the hijacked super-enhancer complex in EVI1-rearranged leukemia (RNA-Seq)

Project description:Chromosomal aberrations in acute myeloid leukemia (AML), such as inv(3) and t(3;3), lead to deregulation of the EVI1 oncogene by the GATA2 distal hematopoietic enhancer (G2DHE). In this project, we aimed to study the transcription factor complexes involved in the regulation of the G2DHE sequence. We have identified PARPi as a member of the G2DHE complex. Here, we used RNA-Seq to analyze transcriptomic changes after PARP inhibition with olaparib and talazoparib and to compare those to EVI1 knockdown.

2021-04-27 | GSE167005 | GEO

Identification of therapeutic targets of the hijacked super-enhancer complex in EVI1-rearranged leukemia (4C-Seq)

Project description:Chromosomal aberrations in acute myeloid leukemia (AML), such as inv(3) and t(3;3), lead to deregulation of the EVI1 oncogene by the GATA2 distal hematopoietic enhancer (G2DHE). In this project, we aimed to study the transcription factor complexes involved in the regulation of the G2DHE sequence. We identified PARP1 as an interactor of G2DHE-associated transcription factors. In this dataset, we studied the interaction of genomic loci between the EVI1 promoter and G2DHE by 4C-Seq in the 3q-rearranged AML cell line MUTZ-3 treated with the PARP1 inhibitors olaparib, talazoparib or the DMSO vehicle control for 24 h.

2021-04-27 | GSE153306 | GEO

Identification of therapeutic targets of the hijacked super-enhancer complex in EVI1-rearranged leukemia (ChIP-Seq)

Project description:Chromosomal aberrations in acute myeloid leukemia (AML), such as inv(3) and t(3;3), lead to deregulation of the EVI1 oncogene by the GATA2 distal hematopoietic enhancer (G2DHE). In this project, we aimed to study the transcription factor complexes involved in the regulation of the G2DHE sequence. In silico and in vitro analyses revealed that binding sites for CEBPA are critical for G2DHE function. Here, we used ChIP-Seq to show association of the CEBPA transcription factor with the G2DHE sequence in the 3q-rearranged cell line MOLM-1

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Identification of therapeutic targets of the hijacked super-enhancer complex in EVI1-rearranged leukemia

Project description:Identification of therapeutic targets of the hijacked super-enhancer complex in EVI1-rearranged leukemia

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Identification of therapeutic targets of the hijacked super-enhancer complex in EVI1-rearranged leukemia (4C-Seq)

Project description:Identification of therapeutic targets of the hijacked super-enhancer complex in EVI1-rearranged leukemia (4C-Seq)

| PRJNA642240 | ENA

Identification of therapeutic targets of the hijacked super-enhancer complex in EVI1-rearranged leukemia (RNA-Seq)

Project description:Identification of therapeutic targets of the hijacked super-enhancer complex in EVI1-rearranged leukemia (RNA-Seq)

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Identification of therapeutic targets of the hijacked super-enhancer complex in EVI1-rearranged leukemia (ChIP-Seq)

Project description:Identification of therapeutic targets of the hijacked super-enhancer complex in EVI1-rearranged leukemia (ChIP-Seq)

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Aberrant EVI1 splicing contributes to EVI1-rearranged leukemia.

Project description:Detailed genomic and epigenomic analyses of MECOM (the MDS1 and EVI1 complex locus) have revealed that inversion or translocation of chromosome 3 drives inv(3)/t(3;3) myeloid leukemias via structural rearrangement of an enhancer that upregulates transcription of EVI1. Here, we identify a novel, previously unannotated oncogenic RNA-splicing derived isoform of EVI1 that is frequently present in inv(3)/t(3;3) acute myeloid leukemia (AML) and directly contributes to leukemic transformation. This EVI1 isoform is generated by oncogenic mutations in the core RNA splicing factor SF3B1, which is mutated in >30% of inv(3)/t(3;3) myeloid neoplasm patients and thereby represents the single most commonly cooccurring genomic alteration in inv(3)/t(3;3) patients. SF3B1 mutations are statistically uniquely enriched in inv(3)/t(3;3) myeloid neoplasm patients and patient-derived cell lines compared with other forms of AML and promote mis-splicing of EVI1 generating an in-frame insertion of 6 amino acids at the 3' end of the second zinc finger domain of EVI1. Expression of this EVI1 splice variant enhanced the self-renewal of hematopoietic stem cells, and introduction of mutant SF3B1 in mice bearing the humanized inv(3)(q21q26) allele resulted in generation of this novel EVI1 isoform in mice and hastened leukemogenesis in vivo. The mutant SF3B1 spliceosome depends upon an exonic splicing enhancer within EVI1 exon 13 to promote usage of a cryptic branch point and aberrant 3' splice site within intron 12 resulting in the generation of this isoform. These data provide a mechanistic basis for the frequent cooccurrence of SF3B1 mutations as well as new insights into the pathogenesis of myeloid leukemias harboring inv(3)/t(3;3).

| S-EPMC9412007 | biostudies-literature

Aberrant EVI1 splicing contributes to EVI1-rearranged leukemia

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-06-21 | GSE190656 | GEO