Dataset Information

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

ABSTRACT: 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.

OTHER RELATED OMICS DATASETS IN: GSE118963

INSTRUMENT(S): Orbitrap Fusion ETD

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Blood Cell, Bone Marrow

DISEASE(S): Acute Leukemia

SUBMITTER: Erwin Schoof

LAB HEAD: Bo T. Porse

PROVIDER: PXD011359 | Pride | 2019-08-08

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	20160201_FS_ES_KU_CEBPa_P30_GMP_rep1_3_I.raw	Raw
	20160201_FS_ES_KU_CEBPa_P30_GMP_rep1_3_II.raw	Raw
	20160201_FS_ES_KU_CEBPa_P30_GMP_rep1_6_I.raw	Raw
	20160201_FS_ES_KU_CEBPa_P30_GMP_rep1_6_II.raw	Raw
	20160201_FS_ES_KU_CEBPa_P30_preGM_rep1_3_I.raw	Raw

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Publications

Mutant CEBPA directly drives the expression of the targetable tumor-promoting factor CD73 in AML.

Jakobsen Janus S JS Laursen Linea G LG Schuster Mikkel B MB Pundhir Sachin S Schoof Erwin E Ge Ying Y d'Altri Teresa T Vitting-Seerup Kristoffer K Rapin Nicolas N Gentil Coline C Jendholm Johan J Theilgaard-Mönch Kim K Reckzeh Kristian K Bullinger Lars L Döhner Konstanze K Hokland Peter P Fitzgibbon Jude J Porse Bo T BT

Science advances 20190710 7

The key myeloid transcription factor (TF), CEBPA, is frequently mutated in acute myeloid leukemia (AML), but the direct molecular effects of this leukemic driver mutation remain elusive. To investigate <i>CEBPA</i> mutant AML, we performed microscale, in vivo chromatin immunoprecipitation sequencing and identified a set of aberrantly activated enhancers, exclusively occupied by the leukemia-associated CEBPA-p30 isoform. Comparing gene expression changes in human <i>CEBPA</i> mutant AML and the c ...[more]

PMID: 31309149

Similar Datasets

Project description:The CCAAT enhancer binding protein alpha (C/EBPalpha) transcription factor plays a key role in the regulation of growth and differentiation of the granulocytic lineage in the hematopoietic system and CEBPA (encoding C/EBPalpha) is often mutated or deregulated in AML patients. Consistently, mice lacking C/EBPalpha have no mature neutrophils and die within a few hours. However, homozygous knockin mice in which wild type Cebpa has been replaced with a mutant allele (BRM2), which abolish the growth-repressing ability of C/EBPalpha, are viable, but at 8 weeks of age they display myeloid dysplasia with absence of neutrophil granulocytes. Strikingly, in older CebpaBRM2/BRM2 knockin mice the myeloid dysplastic phenotype progress into other myeloid malignancies such as myeloid proliferative syndrome and acute myeloid leukemia-like malignancy. This strongly suggests that secondary mutations in other loci must occur when developing leukemia in the CebpaBRM2/BRM2. In order to identify genes that cooperate with Cebpa mutations in the development of leukemia in CebpaBRM2/BRM2 mice a so-called retroviral insertion mutagenesis screen was performed. Inbred newborn CebpaBRM2/BRM2 and wildtype mice were injected with SRS19-6 retrovirus, which incorporated into the genome and resulted in activation of oncogenes and leukemic progression. When leukemia was evident the mice were euthanized and analyzed. As expected the CebpaBRM2/BRM2 mice had a shorter latency than wildtype mice (186 vs. 276 days). The mice had enlarged spleen, thymus, and/or lymph nodes and were thoroughly investigated by histology, flow cytometry and southern in order to determine the leukemic phenotypes. Most of the CebpaBRM2/BRM2 mice developed an AML-like phenotype, whereas T cell leukemias were most prominent in wildtype mice, showing that mutating Cebpa specifically directs leukemic progression towards a myeloid direction. Genomic instability was analyzed by CGH. Finally, the retroviral insertion loci were identified through a splinkerette-aided PCR strategy. This led to the identification of several novel putative and previously unexplored oncogenes, which might collaborate with mutated Cebpa in the development of AML. Keywords: Disease state analysis In order to identify genes that cooperate with Cebpa mutations in the development of leukemia in CebpaBRM2/BRM2 mice a so-called retroviral insertion mutagenesis screen was performed. Inbred newborn CebpaBRM2/BRM2 and wildtype mice were injected with SRS19-6 retrovirus, which incorporated into the genome and resulted in activation of oncogenes and leukemic progression. When leukemia was evident the mice were euthanized and analyzed. GDNA from tumour tissues were analyzed by CGH using tail gDNA as reference.