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 reviewedTranscription 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.
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 |