Mechanistic insights into chromatin targeting by leukemic NUP98-PHF23 fusion

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.

Medienart:

E-Artikel

Erscheinungsjahr:

2020

Erschienen:

2020

Enthalten in:

Zur Gesamtaufnahme - volume:11

Enthalten in:

Nature communications - 11(2020), 1 vom: 03. Juli, Seite 3339

Sprache:

Englisch

Beteiligte Personen:

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

Links:

Volltext

Themen:

Antigens, Nuclear
Chromatin
Disulfiram
EC 1.14.11.-
EC 1.14.11.27
Fetal Alzheimer antigen
Histone H3 trimethyl Lys4
Histones
Homeodomain Proteins
Journal Article
KDM5A protein, human
Nerve Tissue Proteins
Nuclear Pore Complex Proteins
Nup98 protein, human
Oncogene Proteins, Fusion
PHF23 protein, human
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Retinoblastoma-Binding Protein 2
TR3MLJ1UAI
Transcription Factors

Anmerkungen:

Date Completed 31.08.2020

Date Revised 05.01.2024

published: Electronic

Citation Status MEDLINE

doi:

10.1038/s41467-020-17098-4

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM311984827