Pharmacological inhibition of the transcription factor PU.1 in leukemia

The Journal of Clinical Investigation
Iléana Antony-DebréUlrich Steidl

Abstract

The transcription factor PU.1 is often impaired in patients with acute myeloid leukemia (AML). Here, we used AML cells that already had low PU.1 levels and further inhibited PU.1 using either RNA interference or, to our knowledge, first-in-class small-molecule inhibitors of PU.1 that we developed specifically to allosterically interfere with PU.1-chromatin binding through interaction with the DNA minor groove that flanks PU.1-binding motifs. These small molecules of the heterocyclic diamidine family disrupted the interaction of PU.1 with target gene promoters and led to downregulation of canonical PU.1 transcriptional targets. shRNA or small-molecule inhibition of PU.1 in AML cells from either PU.1lo mutant mice or human patients with AML-inhibited cell growth and clonogenicity and induced apoptosis. In murine and human AML (xeno)transplantation models, treatment with our PU.1 inhibitors decreased tumor burden and resulted in increased survival. Thus, our study provides proof of concept that PU.1 inhibition has potential as a therapeutic strategy for the treatment of AML and for the development of small-molecule inhibitors of PU.1.

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Citations

Oct 9, 2018·Nucleic Acids Research·Amanda V AlbrechtGregory M K Poon
Mar 31, 2019·Medicinal Research Reviews·Michael HsingArtem Cherkasov
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Datasets Mentioned

BETA
GSE13125
GSE1159
GSE63317
GSE77651

Methods Mentioned

BETA
MDS
footprinting
biosensor
chip
transfection
reverse transcription PCR
ChIP-seq
FACS
flow cytometry
pulldown

Software Mentioned

Ingenuity Pathway Analysis ( IPA
GraphPad
GraphPad Prism
ARACNe
Affymetrix
Transcriptome Analysis Console
GSEA
Expression Console

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