Mechanistic insights into chromatin targeting by leukemic NUP98-PHF23 fusion

Yi Zhang,Jinyong Zhang,Xiaobing Shi,Kuai Li,Gang Greg Wang,Sheryl M Gough,Peter D Aplan,Ling Cai,Tatiana G Kutateladze,Yiran Guo,Kendra R Vann

doi:10.1038/s41467-020-17098-4

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.

Highlights

Chromosomal nucleoporin 98 (NUP98)-PHF23 translocation is associated with an aggressive form of acute myeloid leukemia (AML) and poor survival rate
The NUP98–PHF23 fusion was originally identified as a cryptic translocation in AML in 200714, and like other NUP98 fusion chimeras, NUP98–PHF23 translocation is associated with an aggressive disease course and poor survival[15]
We have previously shown that the expression of NUP98–PHF23 fusion leads to myeloid, erythroid, T-cell, and B-cell leukemia in mice, and that the treatment of NUP98–PHF23 cells with a small molecule compound disulfiram (DS) results in death of cells expressing NUP98–PHF23, likely due to disruption of the histone-binding activity of the PHF23 plant homeodomain (PHD) finger[9]

Summary

Introduction

Chromosomal NUP98-PHF23 translocation is associated with an aggressive form of acute myeloid leukemia (AML) and poor survival rate. Posttranslational modifications (PTMs) of histones provide fundamental mechanisms for modulating gene expression and determining cellular identities during organismal development and cell lineage specification. Misregulation of these mechanisms is associated with a number of human diseases, including acute myeloid leukemia (AML)[1]. We have previously shown that the expression of NUP98–PHF23 fusion leads to myeloid, erythroid, T-cell, and B-cell leukemia in mice, and that the treatment of NUP98–PHF23 cells with a small molecule compound disulfiram (DS) results in death of cells expressing NUP98–PHF23, likely due to disruption of the histone-binding activity of the PHF23 plant homeodomain (PHD) finger[9]. Despite the critical role of NUP98–PHF23 in leukemogenesis, which emphasizes the urgent need to develop chemotypes targeting this chimera, the structure–function relationship of PHF23 remains poorly characterized

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Results

Conclusion