Proteomics,Multiomics

Dataset Information

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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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Publications


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]

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