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Identification of transcripts regulated by CEBPA protein and its P30 isoform in K562

ABSTRACT: To investigate the effect of CEBPA and its mutant isoform P30 on the expression of mRNAs and long non-coding RNAs (lncRNAs), we utilized the K562 AML cell line carrying a stable and Tet-on inducible CEBPA or P30 allele.

ORGANISM(S): Homo sapiens

PROVIDER: GSE65235 | GEO | 2015/06/10

SECONDARY ACCESSION(S): PRJNA273465

REPOSITORIES: GEO

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Identification of transcripts regulated by CEBPA protein and its P30 isoform in K562

Project description:To investigate the effect of CEBPA and its mutant isoform P30 on the expression of mRNAs and long non-coding RNAs (lncRNAs), we utilized the K562 AML cell line carrying a stable and Tet-on inducible CEBPA or P30 allele. Based on the expression of known CEBPA transcriptional targets, we selected RNA extracted from 48 hours of induction (CEBPA or P30) together with RNA extracted from control-induced cells (CTR). 2 biological replicates for each sample have been utilized.

2015-06-10 | E-GEOD-65235 | biostudies-arrayexpress

The p30 isoform of CEBPA uncovers a silent enhancer to drive the expression of the tumor promoting factor CD73 in CEBPA mutant AML

Project description:The key myeloid transcription factor (TF) CEBPA is frequently mutated in acute myeloid leukemia (AML), but the molecular ramifications of this leukemic driver mutation remain elusive. To investigate CEBPA mutant AML, we compared gene expression changes in human CEBPA mutant AML and in the corresponding CebpaLp30 mouse model, and identified a conserved cross-species transcriptional program. ChIP-seq revealed aberrantly activated enhancers, exclusively occupied by the leukemia-associated CEBPA-p30 isoform. One leukemic-enhancer upstream of Nt5e, encoding CD73, was physically and functionally linked to this conserved AML gene, and could be activated by CEBPA. Targeting of CD73-adenosine signaling increased AML survival in transplanted mice. Our data indicate a first-in-class link between a TF cancer driver mutation and a druggable, direct transcriptional target.

2019-08-08 | PXD011359 | Pride

Identification of transcripts regulated by CEBPA in K562

2014-09-01 | GSE58743 | GEO

Effects of CEBPA isoform expression on NB4 cells

Project description:Here we investigated the effects of CEBPA transcription factor expression on myeloid NB4 cells. The sequence of rat CEBPA was C-terminally fused to a promiscuous biotin ligase tag (BirA*) and NB4 cell lines were engineered to express the fusion protein under the control of a doxycycline inducible promoter. Three different NB4 cell lines were investigated that expressed (i) BirA* tag alone (ii) full length CEBPA isoform (P42) fused to BirA* (iii) truncated CEBPA isoform (P30) fused to BirA*. Cells were seeded in media supplemented with or without doxycycline.

2021-06-26 | E-MTAB-9947 | biostudies-arrayexpress

Identification of transcripts regulated by CEBPA in K562

Project description:To investigate the effect of CEBPA on the expression of mRNAs and long non-coding RNAs ( lncRNAs), we utilized the K562 AML cell line carrying a stable and Tet-on inducible CEBPA allele. K562 cells lack endogenous CEBPA and restoration of its expression induces proliferation arrest and granulocytic differentiation . Based on the expression of known CEBPA transcriptional targets, we selected RNA extracted from 48 hours of induction (CEBPA) together with RNA extracted from control-induced cells (CTR). 4 biological replicates for each sample have been utilized.

2014-09-01 | E-GEOD-58743 | biostudies-arrayexpress

The p30 isoform of CEBPA uncovers a silent enhancer to drive the expression of the tumor promotive factor CD73 in CEBPA mutant AML

Project description:CEBPA is a key hematopoietic transcription factor (TF), found mutated in 5-14% of all acute myeloid leukemia (AML) cases, but the direct molecular ramifications of this driver mutation remains elusive. To investigate CEBPA-mutant AML, we compared patient aberrant genetic programs with changes in a precise mouse model (Lp30) expressing only the cancer-prevalent truncated CEBPA, p30, and identified a stringent cross-species AML program. Small-scale ChIP-seq methodology revealed aberrantly activated enhancers, exclusively occupied by CEBPA in leukemia. One cancer-enhancer upstream of Nt5e, encoding CD73, was physically and functionally linked to this conserved AML gene, and could be activated by CEBPA. Targeting of CD73-adenosine signaling increased survival in AML transplanted mice. Our data thus indicate a first-in-class link between a TF cancer driver mutation and a druggable, direct transcriptional target.

2019-07-30 | GSE118963 | GEO

CEBPA-mutated leukemia is sensitive to genetic and pharmacological inhibition of the MLL complex

Project description:The gene encoding the transcription factor C/EBPα is mutated in 10-15% of all patients with de novo acute myeloid leukemia (AML). N-terminal CEBPA mutations cause selective ablation of full-length C/EBPα without affecting the expression of a shorter oncogenic isoform, termed p30. The mechanistic basis of p30-induced leukemogenesis is not well understood. Here, we show that the SET/MLL histone methyltransferase complex represents a critical actionable vulnerability in CEBPA-mutated AML. The oncogenic C/EBPα p30 isoform and MLL show global co-localization on chromatin and core SET/MLL complex components exhibit robust physical interaction with p30. We also show that C/EBPα p30-expressing cells require the expression of an intact MLL protein, as targeted CRISPR/Cas9-mediated mutagenesis results in proliferation arrest and myeloid differentiation. In line with this, CEBPA-mutated hematopoietic progenitor cells are hypersensitive to pharmacological inhibition of the SET/MLL complex. SET/MLL complex inhibition impairs proliferation, induces cell cycle arrest and causes apoptosis in mouse and human AML cells with CEBPA mutations. Global analysis of gene expression changes shows that inhibitor treatment restores myeloid differentiation potential in CEBPA-mutated cells. Finally, we identify the transcription factor GATA2 as a direct critical target of the cooperative gene regulation between p30 and MLL in CEBPA-mutated AML. Taken together, we show that C/EBPα p30 requires the SET/MLL complex to regulate oncogenic gene expression and that CEBPA-mutated AML is hypersensitive to perturbation of the SET/MLL complex. These findings expand our understanding of CEBPA-mutated AML and identify the SET/MLL complex as a potential therapeutic target in this disease.

2019-01-29 | GSE117780 | GEO

The p30 isoform of CEBPA uncovers a silent enhancer to drive the expression of the tumor promotive factor CD73 in CEBPA mutant AML

Project description:The p30 isoform of CEBPA uncovers a silent enhancer to drive the expression of the tumor promotive factor CD73 in CEBPA mutant AML

| PRJNA487543 | ENA

Arginine methylationof the p30 C/EBPα oncoprotein regulates progenitor proliferationand myeloid differentiation

Project description:The transcription factor CCAAT enhancer binding protein alpha (C/EBPα) is a master regulator of myelopoiesis. CEBPA encodes a long (p42) and a truncated (p30) protein isoform from a single mRNA. Mutations that abnormally enhance expression of p30 are associated with acute myelogenous leukemia (AML). We show by mutational analysis that three highly conserved arginine residues (R140,147,154) located at the p30 C/EBPα N-terminus, previously found to be methylated, are involved in myeloid lineage commitment, progenitor proliferation, and differentiation. The conservative amino acid substitution with lysine that retains the amino acid side chain charge enhanced progenitor proliferation, while a non-conservative substitution with uncharged side chains (alanine or leucine) impaired proliferation and enhanced granulopoietic differentiation. Analysis of protein-protein interactions (PPI) suggested that arginine methylation of p30 C/EBPα differentially determines its capacity to interact with SWI/SNF and MLL complexes. Pharmacological targeting of p30 C/EBPα arginine methylation may have clinical relevance in myeloproliferative and inflammatory diseases, in neutropenia, and in leukemic stem cells.

2024-11-20 | GSE266544 | GEO

Lenalidomide-mediated enhanced translation of C/EBP?-p30 protein upregulates expression of the anti-leukemic microRNA-181a in acute myeloid leukemia - microRNA Data

Project description:Recently, we showed that increased miR-181a expression was associated with improved outcomes in cytogenetically normal acute myeloid leukemia (CN-AML). Interestingly, miR-181a expression was increased in CN-AML patients harboring CEBPA mutations, which are usually biallelic and associate with better prognosis. CEBPA encodes the C/EBP? transcription factor. We demonstrate here that the presence of N-terminal CEBPA mutations and miR-181a expression are linked. Indeed, the truncated C/EBP?-p30 isoform, which is produced from the N-terminal mutant CEBPA gene or from the differential translation of wild-type CEBPA mRNA and is commonly believed to have no transactivation activity, binds to the miR-181a-1 promoter and upregulates the microRNA expression. In xenograft mouse models, ectopic miR-181a expression inhibits tumor growth. This regulatory pathway may explain an increased sensitivity to apoptosis-inducing chemotherapy in subsets of AML patients. Altogether, our data provide a potential explanation for the improved clinical outcomes observed in CEBPA-mutated CN-AML patients.

2012-10-04 | E-MTAB-1320 | biostudies-arrayexpress

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