Pharmacological inhibition of the transcription factor PU.1 in leukemia

Iléana Antony-Debré, Ananya Paul, Joana Leite, Kelly Mitchell, Hye Mi Kim, Luis A. Carvajal, Tihomira I. Todorova, Kenneth Huang, Arvind Kumar, Abdelbasset A. Farahat, Boris A. Bartholdy, Swathi-Rao Narayanagari, Jiahao Chen, Alberto Ambesi-Impiombato, Adolfo A. Ferrando, Ioannis Mantzaris, Evripidis Gavathiotis, Amit K. Verma, Britta Will, David W. BoykinW. David Wilson, Gregory M.K. Poon, Ulrich G. Steidl

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30 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4297-4313
Number of pages17
JournalJournal of Clinical Investigation
Volume127
Issue number12
DOIs
StatePublished - Dec 1 2017

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ASJC Scopus subject areas

  • Medicine(all)

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Antony-Debré, I., Paul, A., Leite, J., Mitchell, K., Kim, H. M., Carvajal, L. A., Todorova, T. I., Huang, K., Kumar, A., Farahat, A. A., Bartholdy, B. A., Narayanagari, S-R., Chen, J., Ambesi-Impiombato, A., Ferrando, A. A., Mantzaris, I., Gavathiotis, E., Verma, A. K., Will, B., ... Steidl, U. G. (2017). Pharmacological inhibition of the transcription factor PU.1 in leukemia. Journal of Clinical Investigation, 127(12), 4297-4313. https://doi.org/10.1172/JCI92504