Transcription factor reorganization at chromatin secures myeloid progenitor cell survival in PU.1 downregulated leukemia [shRNAscreen]

ABSTRACT: Transcription factors (TFs) orchestrating lineage-development also control genes required for cellular survival. One such TF is PU.1, which is essential for myeloid development. Mice with downregulated PU.1 levels develop fatal acute myeloid leukemia (AML). However, because PU.1 is required for expression of growth factor receptors and signaling molecules, it has been unclear how PU.1-downregulated progenitors survive long enough to acquire additional alterations promoting leukemic transformation. Combining a multi-omics approach with a functional genetic screen, we reveal herein that growth of PU.1-downregulated progenitors is secured by shifting survival control from cytokine-dependency towards overactivation of an autophagy-predominated stem cell program. This shift (for which we also find evidence in human AML) is linked to redirected binding of the PU.1 partner TF RUNX1 to chromatin sites previously not co-bound by PU.1. Hence, partner TF reallocation at chromatin can induce autophagy as a cell-autonomous failsafe mechanism to rescue cells from survival deficits caused by TF loss. Such growth-compensatory effects should be taken into account when considering TF as targets in cancer therapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE250630 | GEO | 2024/11/15

REPOSITORIES: GEO