2. Academic Validation
  3. Pharmacological inhibition of the transcription factor PU.1 in leukemia

Pharmacological inhibition of the transcription factor PU.1 in leukemia

  • J Clin Invest. 2017 Dec 1;127(12):4297-4313. doi: 10.1172/JCI92504.
Iléana Antony-Debré 1,  Ananya Paul 2,  Joana Leite 1,  Kelly Mitchell 1,  Hye Mi Kim 2,  Luis A Carvajal 1,  Tihomira I Todorova 1,  Kenneth Huang 2,  Arvind Kumar 2,  Abdelbasset A Farahat 2 3,  Boris Bartholdy 1,  Swathi-Rao Narayanagari 1,  Jiahao Chen 1,  Alberto Ambesi-Impiombato 4,  Adolfo A Ferrando 4,  Ioannis Mantzaris 5,  Evripidis Gavathiotis 6 7 8,  Amit Verma 5 7 8,  Britta Will 1 7 8,  David W Boykin 2,  W David Wilson 2,  Gregory Mk Poon 2,  Ulrich Steidl 1 5 7 8
Affiliations

Affiliations

  • 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.
PMID: 29083320 DOI: 10.1172/JCI92504
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.

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