Redistribution of PU.1 partner transcription factor RUNX1 binding secures cell survival during leukemogenesis

Bender, Alexander Boydere, Füsun Jayavelu, Ashok Kumar Tibello, Alessia König, Thorsten Aleth, Hanna Meyer zu Hörste, Gerd Vogl, Thomas Rosenbauer, Frank

Research article (journal) | Peer reviewed

Abstract

Transcription factors (TFs) orchestrating lineage-development often control genes required for cellular survival. However, it is not well understood how cells survive when such TFs are lost, for example in cancer. PU.1 is an essential TF for myeloid fate, and mice with downregulated PU.1 levels develop acute myeloid leukemia (AML). Combining a multi-omics approach with a functional genetic screen, we reveal that PU.1-downregulated cells fundamentally change their survival control from cytokine-driven pathways to overexpression of an autophagy-predominated stem cell gene program, for which we also find evidence in human AML. Control of this program involves redirected chromatin occupancy of the PU.1 partner TF Runx1 to a lineage-inappropriate binding site repertoire. Hence, genomic reallocation of TF binding upon loss of a partner TF can act as a pro-oncogenic failsafe mechanism by sustaining cell survival during leukemogenesis.

Details about the publication

JournalThe EMBO Journal
Volume43
Page range6291-6309
StatusPublished
Release year2024 (14/11/2024)
Language in which the publication is writtenEnglish
DOI10.1038/s44318-024-00295-y
Link to the full texthttps://www.embopress.org/doi/full/10.1038/s44318-024-00295-y
KeywordsLeukemia, PU.1, Transcription Factors

Authors from the University of Münster

Aleth, Hanna
Institute of Molecualr Tumor Biology
Bender, Alexander
Institute of Molecualr Tumor Biology
Meyer zu Hörste, Gerd Heinrich Rudolf
Department for Neurology
Rosenbauer, Frank
Institute of Molecualr Tumor Biology
Tibello, Alessia Antonia
Institute of Molecualr Tumor Biology