Mechanistic insights into chromatin targeting by leukemic NUP98-PHF23 fusion

Yi Zhang, Yiran Guo, Sheryl M. Gough, Jinyong Zhang, Kendra R. Vann, Kuai Li, Ling Cai, Xiaobing Shi, Peter D. Aplan, Gang Greg Wang and Tatiana G. Kutateladze ()
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Yi Zhang: University of Colorado School of Medicine
Yiran Guo: The University of North Carolina School of Medicine
Sheryl M. Gough: National Cancer Institute, NIH
Jinyong Zhang: University of Colorado School of Medicine
Kendra R. Vann: University of Colorado School of Medicine
Kuai Li: Van Andel Research Institute
Ling Cai: The University of North Carolina School of Medicine
Xiaobing Shi: Van Andel Research Institute
Peter D. Aplan: National Cancer Institute, NIH
Gang Greg Wang: The University of North Carolina School of Medicine
Tatiana G. Kutateladze: University of Colorado School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-10

Abstract: Abstract Chromosomal NUP98-PHF23 translocation is associated with an aggressive form of acute myeloid leukemia (AML) and poor survival rate. Here, we report the molecular mechanisms by which NUP98-PHF23 recognizes the histone mark H3K4me3 and is inhibited by small molecule compounds, including disulfiram that directly targets the PHD finger of PHF23 (PHF23PHD). Our data support a critical role for the PHD fingers of NUP98-PHF23, and related NUP98-KDM5A and NUP98-BPTF fusions in driving leukemogenesis, and demonstrate that blocking this interaction in NUP98-PHF23 expressing AML cells leads to cell death through necrotic and late apoptosis pathways. An overlap of NUP98-KDM5A oncoprotein binding sites and H3K4me3-positive loci at the Hoxa/b gene clusters and Meis1 in ChIP-seq, together with NMR analysis of the H3K4me3-binding sites of the PHD fingers from PHF23, KDM5A and BPTF, suggests a common PHD finger-dependent mechanism that promotes leukemogenesis by this type of NUP98 fusions. Our findings highlight the direct correlation between the abilities of NUP98-PHD finger fusion chimeras to associate with H3K4me3-enriched chromatin and leukemic transformation.

Date: 2020
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DOI: 10.1038/s41467-020-17098-4

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