TY - JOUR
T1 - Pharmacological inhibition of the transcription factor PU.1 in leukemia
AU - Antony-Debré, Iléana
AU - Paul, Ananya
AU - Leite, Joana
AU - Mitchell, Kelly
AU - Kim, Hye Mi
AU - Carvajal, Luis A.
AU - Todorova, Tihomira I.
AU - Huang, Kenneth
AU - Kumar, Arvind
AU - Farahat, Abdelbasset A.
AU - Bartholdy, Boris
AU - Narayanagari, Swathi Rao
AU - Chen, Jiahao
AU - Ambesi-Impiombato, Alberto
AU - Ferrando, Adolfo A.
AU - Mantzaris, Ioannis
AU - Gavathiotis, Evripidis
AU - Verma, Amit
AU - Will, Britta
AU - Boykin, David W.
AU - Wilson, W. David
AU - Poon, Gregory M.K.
AU - Steidl, Ulrich
N1 - Funding Information:
We thank A. Skoultchi, K. Gritsman, J.B. Micol, and all members of the Steidl laboratory for helpful suggestions and discussions, and M. Ferreira for technical assistance. We also thank D. Sun from the Einstein Stem Cell Isolation and Xenotransplantation Facility (funded through New York Stem Cell Science [NYSTEM] grant C029154); D. Reynolds and W. Tran from the Einstein Genomics Core Facility; P. Schultes from the Department of Cell Biology at Albert Einstein College of Medicine; and S. Wang from the Georgia State University Mass Spectrometry facility for their expert technical support. We thank the Albert Einstein Cancer Center Shared Resources (NIH grant P30CA013330) and the Herbert Irving Cancer Center Shared Resources (NIH grant P30CA013696). This work was supported by NIH grants R01CA166429 and R01CA217092 (to US), R01GM111749 (to WDW and DWB), and R21HL129063 (to GMKP); a Translational Research Program (TRP) grant from the Leukemia & Lymphoma Society (to US); and a research grant from the Taub Foundation for Myelodysplastic Syndromes (MDS) Research (to US). IAD was partially supported by a postdoctoral fellowship from the Association pour la Recherche sur le Cancer. JC was supported by the Einstein Training Program in Stem Cell Research from the Empire State Stem Cell Fund through New York State Department of Health contract C30292GG. US is the Diane and Arthur B. Belfer Scholar in Cancer Research of the Albert Einstein College of Medicine and is a Research Scholar of the Leukemia &Lymphoma Society. AF is supported by NIH grant R35CA210065.
Funding Information:
We thank A. Skoultchi, K. Gritsman, J.B. Micol, and all members of the Steidl laboratory for helpful suggestions and discussions, and M. Ferreira for technical assistance. We also thank D. Sun from the Einstein Stem Cell Isolation and Xenotransplantation Facility (funded through New York Stem Cell Science [NYSTEM] grant C029154); D. Reynolds and W. Tran from the Einstein Genomics Core Facility; P. Schultes from the Department of Cell Biology at Albert Einstein College of Medicine; and S. Wang from the Georgia State University Mass Spectrometry facility for their expert technical support. We thank the Albert Einstein Cancer Center Shared Resources (NIH grant P30CA013330) and the Herbert Irving Cancer Center Shared Resources (NIH grant P30CA013696). This work was supported by NIH grants R01CA166429 and R01CA217092 (to US), R01GM111749 (to WDW and DWB), and R21HL129063 (to GMKP); a Translational Research Program (TRP) grant from the Leukemia & Lymphoma Society (to US); and a research grant from the Taub Foundation for Myelodysplastic Syndromes (MDS) Research (to US). IAD was partially supported by a postdoctoral fellowship from the Association pour la Recherche sur le Cancer. JC was supported by the Einstein Training Program in Stem Cell Research from the Empire State Stem Cell Fund through New York State Department of Health contract C30292GG. US is the Diane and Arthur B. Belfer Scholar in Cancer Research of the Albert Einstein College of Medicine and is a Research Scholar of the Leukemia & Lymphoma Society. AF is supported by NIH grant R35CA210065.
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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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U2 - 10.1172/JCI92504
DO - 10.1172/JCI92504
M3 - Article
C2 - 29083320
AN - SCOPUS:85037141449
SN - 0021-9738
VL - 127
SP - 4297
EP - 4313
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 12
ER -