Diagenode

The ETO2 transcriptional cofactor maintains acute leukemia by driving a MYB/EP300-dependent stemness program


Fagnan A. et al.

Transcriptional cofactors of the ETO family are recurrent fusion partners in acute leukemia. We characterized the ETO2 regulome by integrating transcriptomic and chromatin binding analyses in human erythroleukemia xenografts and controlled ETO2 depletion models. We demonstrate that beyond its well-established repressive activity, ETO2 directly activates transcription of MYB, among other genes. The ETO2-activated signature is associated with a poorer prognosis in erythroleukemia but also in other acute myeloid and lymphoid leukemia subtypes. Mechanistically, ETO2 colocalizes with EP300 and MYB at enhancers supporting the existence of an ETO2/MYB feedforward transcription activation loop (e.g., on MYB itself). Both small-molecule and PROTAC-mediated inhibition of EP300 acetyltransferases strongly reduced ETO2 protein, chromatin binding, and ETO2-activated transcripts. Taken together, our data show that ETO2 positively enforces a leukemia maintenance program that is mediated in part by the MYB transcription factor and that relies on acetyltransferase cofactors to stabilize ETO2 scaffolding activity.

Tags
IPure kit

Share this article

Published
June, 2024

Source

Products used in this publication

  • default alt
    C03010015
    IPure kit v2

Events

  • FASEB Biological Methylation: Fundamental Mechanisms
    Porto, Portugal
    Jul 28-Aug 1, 2024
 See all events

 


       Site map   |   Contact us   |   Conditions of sales   |   Conditions of purchase   |   Privacy policy