Mutant NPM1 Hijacks Transcriptional Hubs to Maintain Pathogenic Gene Programs in Acute Myeloid Leukemia

Nucleophosmin (NPM1) is a ubiquitously expressed nucleolar protein with a wide range of biological functions. In 30% of acute myeloid leukemia (AML), the terminal exon of NPM1 is often found mutated, resulting in the addition of a nuclear export signal and a shift of the protein to the cytoplasm (NP...

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Published inCancer discovery Vol. 13; no. 3; pp. 724 - 745
Main Authors Wang, Xue Qing David, Fan, Dandan, Han, Qinyu, Liu, Yiman, Miao, Hongzhi, Wang, Xinyu, Li, Qinglan, Chen, Dong, Gore, Haley, Himadewi, Pamela, Pfeifer, Gerd P., Cierpicki, Tomasz, Grembecka, Jolanta, Su, Jianzhong, Chong, Shasha, Wan, Liling, Zhang, Xiaotian
Format Journal Article
LanguageEnglish
Published United States American Association for Cancer Research 01.03.2023
Subjects
Chromatin - genetics
Humans
Leukemia, Myeloid, Acute - drug therapy
Mutation
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Nucleophosmin
Online AccessGet full text
ISSN2159-8274
2159-8290
2159-8290
DOI10.1158/2159-8290.CD-22-0424

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Abstract Nucleophosmin (NPM1) is a ubiquitously expressed nucleolar protein with a wide range of biological functions. In 30% of acute myeloid leukemia (AML), the terminal exon of NPM1 is often found mutated, resulting in the addition of a nuclear export signal and a shift of the protein to the cytoplasm (NPM1c). AMLs carrying this mutation have aberrant expression of the HOXA/B genes, whose overexpression leads to leukemogenic transformation. Here, for the first time, we comprehensively prove that NPM1c binds to a subset of active gene promoters in NPM1c AMLs, including well-known leukemia-driving genes-HOXA/B cluster genes and MEIS1. NPM1c sustains the active transcription of key target genes by orchestrating a transcription hub and maintains the active chromatin landscape by inhibiting the activity of histone deacetylases. Together, these findings reveal the neomorphic function of NPM1c as a transcriptional amplifier for leukemic gene expression and open up new paradigms for therapeutic intervention. NPM1 mutation is the most common mutation in AML, yet the mechanism of how the mutant protein results in AML remains unclear. Here, for the first time, we prove mutant NPM1 directly binds to active chromatin regions and hijacks the transcription of AML-driving genes. See related article by Uckelmann et al., p. 746. This article is highlighted in the In This Issue feature, p. 517.
AbstractList Mutant NPM1 in leukemia obtains neomorphic activity to hijack active HOXA/B and MEIS1 transcription on chromatin via the association of XPO1 and blocks the histone deacetylase activity associated with myeloid differentiation. Nucleophosmin (NPM1) is a ubiquitously expressed nucleolar protein with a wide range of biological functions. In 30% of acute myeloid leukemia (AML), the terminal exon of NPM1 is often found mutated, resulting in the addition of a nuclear export signal and a shift of the protein to the cytoplasm (NPM1c). AMLs carrying this mutation have aberrant expression of the HOXA/B genes, whose overexpression leads to leukemogenic transformation. Here, for the first time, we comprehensively prove that NPM1c binds to a subset of active gene promoters in NPM1c AMLs, including well-known leukemia-driving genes— HOXA/B cluster genes and MEIS1 . NPM1c sustains the active transcription of key target genes by orchestrating a transcription hub and maintains the active chromatin landscape by inhibiting the activity of histone deacetylases. Together, these findings reveal the neomorphic function of NPM1c as a transcriptional amplifier for leukemic gene expression and open up new paradigms for therapeutic intervention.
Nucleophosmin (NPM1) is a ubiquitously expressed nucleolar protein with a wide range of biological functions. In 30% of acute myeloid leukemia (AML), the terminal exon of NPM1 is often found mutated, resulting in the addition of a nuclear export signal and a shift of the protein to the cytoplasm (NPM1c). AMLs carrying this mutation have aberrant expression of the HOXA/B genes, whose overexpression leads to leukemogenic transformation. Here, for the first time, we comprehensively prove that NPM1c binds to a subset of active gene promoters in NPM1c AMLs, including well-known leukemia-driving genes-HOXA/B cluster genes and MEIS1. NPM1c sustains the active transcription of key target genes by orchestrating a transcription hub and maintains the active chromatin landscape by inhibiting the activity of histone deacetylases. Together, these findings reveal the neomorphic function of NPM1c as a transcriptional amplifier for leukemic gene expression and open up new paradigms for therapeutic intervention. NPM1 mutation is the most common mutation in AML, yet the mechanism of how the mutant protein results in AML remains unclear. Here, for the first time, we prove mutant NPM1 directly binds to active chromatin regions and hijacks the transcription of AML-driving genes. See related article by Uckelmann et al., p. 746. This article is highlighted in the In This Issue feature, p. 517.
Nucleophosmin (NPM1) is a ubiquitously expressed nucleolar protein with a wide range of biological functions. In 30% of acute myeloid leukemia (AML), the terminal exon of NPM1 is often found mutated, resulting in the addition of a nuclear export signal and a shift of the protein to the cytoplasm (NPM1c). AMLs carrying this mutation have aberrant expression of the HOXA/B genes, whose overexpression leads to leukemogenic transformation. Here, for the first time, we comprehensively prove that NPM1c binds to a subset of active gene promoters in NPM1c AMLs, including well-known leukemia-driving genes-HOXA/B cluster genes and MEIS1. NPM1c sustains the active transcription of key target genes by orchestrating a transcription hub and maintains the active chromatin landscape by inhibiting the activity of histone deacetylases. Together, these findings reveal the neomorphic function of NPM1c as a transcriptional amplifier for leukemic gene expression and open up new paradigms for therapeutic intervention.Nucleophosmin (NPM1) is a ubiquitously expressed nucleolar protein with a wide range of biological functions. In 30% of acute myeloid leukemia (AML), the terminal exon of NPM1 is often found mutated, resulting in the addition of a nuclear export signal and a shift of the protein to the cytoplasm (NPM1c). AMLs carrying this mutation have aberrant expression of the HOXA/B genes, whose overexpression leads to leukemogenic transformation. Here, for the first time, we comprehensively prove that NPM1c binds to a subset of active gene promoters in NPM1c AMLs, including well-known leukemia-driving genes-HOXA/B cluster genes and MEIS1. NPM1c sustains the active transcription of key target genes by orchestrating a transcription hub and maintains the active chromatin landscape by inhibiting the activity of histone deacetylases. Together, these findings reveal the neomorphic function of NPM1c as a transcriptional amplifier for leukemic gene expression and open up new paradigms for therapeutic intervention.NPM1 mutation is the most common mutation in AML, yet the mechanism of how the mutant protein results in AML remains unclear. Here, for the first time, we prove mutant NPM1 directly binds to active chromatin regions and hijacks the transcription of AML-driving genes. See related article by Uckelmann et al., p. 746. This article is highlighted in the In This Issue feature, p. 517.SIGNIFICANCENPM1 mutation is the most common mutation in AML, yet the mechanism of how the mutant protein results in AML remains unclear. Here, for the first time, we prove mutant NPM1 directly binds to active chromatin regions and hijacks the transcription of AML-driving genes. See related article by Uckelmann et al., p. 746. This article is highlighted in the In This Issue feature, p. 517.
Author Han, Qinyu
Grembecka, Jolanta
Chen, Dong
Wang, Xinyu
Li, Qinglan
Pfeifer, Gerd P.
Miao, Hongzhi
Himadewi, Pamela
Chong, Shasha
Wang, Xue Qing David
Wan, Liling
Liu, Yiman
Fan, Dandan
Zhang, Xiaotian
Cierpicki, Tomasz
Su, Jianzhong
Gore, Haley
AuthorAffiliation 6 Department of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, Texas
3 Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California
5 Department of Pathology, University of Michigan, Ann Arbor, Michigan
1 Department of Epigenetics, Van Andel Research Institute, Grand Rapids, Michigan
2 Institute of Biomedical Big Data, Wenzhou Medical University, Wenzhou, China
4 Department of Cancer Biology and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
AuthorAffiliation_xml – name: 5 Department of Pathology, University of Michigan, Ann Arbor, Michigan
– name: 6 Department of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, Texas
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DocumentTitleAlternate Mutant NPM1 Hijacks Transcription in AML
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J. Su, S. Chong, L. Wan, and X. Zhang jointly supervised this article.
Current address for X.Q.D. Wang: Department of Biochemistry, University of Southern California, Los Angeles, California.
Cancer Discov 2023;13:724–45
Note: X.Q.D. Wang, D. Fan, Q. Han, and Y. Liu contributed equally to this article.
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Brunetti (2023030108202976300_) 2019; 110
Grisendi (2023030108202976300_) 2006; 6
Vassiliou (2023030108202976300_) 2011; 43
Qin (2023030108202976300_) 2020; 11
Li (2023030108202976300_) 2009; 25
Spencer (2023030108202976300_) 2015; 29
36455613 - Cancer Discov. 2023 Mar 1;13(3):746-765. doi: 10.1158/2159-8290.CD-22-0366.
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Snippet Nucleophosmin (NPM1) is a ubiquitously expressed nucleolar protein with a wide range of biological functions. In 30% of acute myeloid leukemia (AML), the...
Mutant NPM1 in leukemia obtains neomorphic activity to hijack active HOXA/B and MEIS1 transcription on chromatin via the association of XPO1 and blocks the...
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StartPage 724
SubjectTerms Chromatin - genetics
Humans
Leukemia, Myeloid, Acute - drug therapy
Mutation
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Nucleophosmin
Title Mutant NPM1 Hijacks Transcriptional Hubs to Maintain Pathogenic Gene Programs in Acute Myeloid Leukemia
URI https://www.ncbi.nlm.nih.gov/pubmed/36455589
https://www.proquest.com/docview/2746392824
https://pubmed.ncbi.nlm.nih.gov/PMC9975662
Volume 13
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