Reader Function a Wide Array of Leukemias Sensitive to Inhibition of PHD Histone PHF23 Is a Chromatin-Modifying Oncoprotein That Causes

In this report, we show that expression of a NUP98–PHF23 ( NP23 ) fusion, associated with acute myeloid leukemia (AML) in humans, leads to myeloid, erythroid, T-cell, and B-cell leukemia in mice. The leukemic and preleukemic tissues display a stem cell–like expression signature, including Hoxa , Hoxb , and Meis1 genes. The PHF23 plant homeodomain (PHD) motif is known to bind to H3K4me3 residues, and chromatin immunoprecipitation experiments demonstrated that the NP23 protein binds to chromatin at a specifi c subset of H3K4me3 sites, including at Hoxa , Hoxb , and Meis1 . Treatment of NP23 cells with disulfi ram, which inhibits the binding of PHD motifs to H3K4me3, rapidly and selectively killed NP23-expressing myeloblasts; cell death was preceded by decreased expression of Hoxa , Hoxb , and Meis1 . Furthermore, AML driven by a related fusion gene, NUP98–JARID1A (NJL), was also sensitive to disulfi ram. Thus, the NP23 mouse provides a platform to evaluate compounds that disrupt binding of oncogenic PHD proteins to H3K4me3. SIGNIFICANCE: NP23 and NJL belong to a subset of chromatin-modifying fusion oncoproteins that cause leukemia characterized by overexpression of Hoxa and Meis1 genes. Inhibition of NP23 binding to H3K4me3 at Hoxa and Meis1 loci by disulfi ram, a U.S. Food and Drug Administration–approved drug, leads to leukemic cell death, demonstrating the feasibility of targeting this subset of oncoproteins. Cancer Discov; 4(5); 1–14. ©2014 AACR. Authors’ Affi liations: 1 Genetics Branch , Center for Cancer Research, National Cancer Institute, NIH, Bethesda; 2 Department of Pathology, Johns Hopkins University, Baltimore, Maryland; 3 Department of Biomolecular Chemistry, University of Wisconsin, Madison, Wisconsin; and 4 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/). Corresponding Author: Peter D. Aplan, Genetics Branch , Center for Cancer Research, National Cancer Institute, NIH, Building 37, Room 6002, 37 Convent Drive, Bethesda, MD 20892. Phone: 301-435-5005; Fax: 301496-0047; E-mail: aplanp@mail.nih.gov doi: 10.1158/2159-8290.CD-13-0419 ©2014 American Association for Cancer Research. on April 24, 2014. © 2014 American Association for Cancer Research. cancerdiscovery.aacrjournals.org Downloaded from Published OnlineFirst February 17, 2014; DOI: 10.1158/2159-8290.CD-13-0419