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J Clin Invest. 2017 Dec 1;127(12):4297-4313. doi: 10.1172/JCI92504. Epub 2017 Oct 30.

Pharmacological inhibition of the transcription factor PU.1 in leukemia.

Author information

1
Department of Cell Biology, Albert Einstein College of Medicine, New York, New York, USA.
2
Department of Chemistry, Georgia State University, Atlanta, Georgia, USA.
3
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
4
Institute for Cancer Genetics, Columbia University, New York, New York, USA.
5
Department of Medicine (Oncology), Division of Hemato-Oncology, Albert Einstein College of Medicine-Montefiore Medical Center, New York, New York, USA.
6
Department of Biochemistry.
7
Albert Einstein Cancer Center, and.
8
Ruth L. and David S. Gottesman Institute for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, New York, New York, USA.

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.

KEYWORDS:

Drug therapy; Hematology; Leukemias; Therapeutics; Transcription

PMID:
29083320
PMCID:
PMC5707147
DOI:
10.1172/JCI92504
[Indexed for MEDLINE]
Free PMC Article

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