Direct pharmacologic regulation of the ETS transcription factor PU.1

Abstract

The ETS‐family transcription factor PU.1 is essential for the self‐renewal of hematopoietic stem cells (HSC) as well as their differentiation to various lineage‐committed hematopoietic progenitors. Specific to the bone marrow niche, PU.1 regulates the expression of several key cytokines (e.g. CXCR4) and their receptors (e.g. GM‐CSF receptor, FLT3) involved in HSC mobilization. Extensive studies have shown that incomplete loss of PU.1 activity, to ~20% wildtype levels, leads to lineage arrest and aggressive leukemic disease. Conversely, lentiviral overexpression of PU.1 resolves the differentiation block in leukemic blasts, and suggests the activation of PU.1 as a potential therapeutic approach. To this end, we have identified by phage display technology a panel of selective PU.1‐binding oligopeptides. Several of these peptides promote PU.1 binding to cognate DNA sites in a dose‐dependent manner and confer resistance to PU.1 against inhibition by netropsin. To determine the essential residues responsible for their activity, we screened a targeted library of truncated hit peptides and found that as few as four residues were sufficient to enhance site‐specific DNA binding by PU.1. These peptide sequences represent leads for developing direct‐acting PU.1‐specific modulators with respect to target DNA binding and interactions with major binding partners. The resulting low‐MW reagents could significantly expand the pharmacology of transcription factors and help overcome barriers in hematopoietic research and therapy that are currently imposed by genetic approaches.Support or Funding InformationSupported by NIH HL129063.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.