Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 127, Issue 12, Pages 4297-4313Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI92504
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Funding
- New York Stem Cell Science [NYSTEM] grant [C029154]
- Albert Einstein Cancer Center Shared Resources (NIH grant) [P30CA013330]
- Herbert Irving Cancer Center Shared Resources (NIH grant) [P30CA013696]
- NIH [R01CA166429, R01CA217092, R01GM111749, R21HL129063, R35CA210065]
- Translational Research Program (TRP) grant from the Leukemia & Lymphoma Society
- Taub Foundation for Myelodysplastic Syndromes (MDS) Research
- Association pour la Recherche sur le Cancer
- Einstein Training Program in Stem Cell Research from the Empire State Stem Cell Fund through New York State Department of Health [C30292GG]
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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 smallmolecule 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.1(lo) mutant mice or human patients with AMLinhibited 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.
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