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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Bibliographic Details
Published in:Cancer discovery 2023-03, Vol.13 (3), p.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: Article
Language:English
Subjects:
Chromatin - genetics
Humans
Leukemia, Myeloid, Acute - drug therapy
Mutation
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Nucleophosmin
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Summary: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.
ISSN:2159-8274
2159-8290
DOI:10.1158/2159-8290.CD-22-0424