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

• DOI: 10.1158/2159-8290.c.6549829.v1
• Publication Date: 2023-04-04T15:31:25Z
• Authors: Xue Qing David Wang; Dandan Fan; Qinyu Han; Yiman Liu; Hongzhi Miao; Xinyu Wang; Qinglan Li; Dong Chen; Haley Gore; Pamela Himadewi; Gerd P. Pfeifer; Tomasz Cierpicki; Jolanta Grembecka; Jianzhong Su; Shasha Chong; Liling Wan; Xiaotian Zhang
• Keywords: NPM1

<div>Abstract<p>Nucleophosmin (NPM1) is a ubiquitously expressed nucleolar protein with wide range of biological functions. In 30% acute myeloid leukemia (AML), the terminal exon <i>NPM1</i> often found mutated, resulting in addition nuclear export signal and shift to cytoplasm (NPM1c). AMLs carrying this mutation have aberrant expression <i>HOXA/B</i> genes, whose overexpression leads leukemogenic transformation. Here, for first time, we comprehensively prove that NPM1c binds subset active gene promoters AMLs, including well-known leukemia-driving genes—<i>HOXA/B</i> cluster genes <i>MEIS1</i>. sustains transcription key target by orchestrating hub maintains chromatin landscape inhibiting activity histone deacetylases. Together, these findings reveal neomorphic function as transcriptional amplifier leukemic open up new paradigms therapeutic intervention.</p>Significance:<p><i>NPM1</i> most common AML, yet mechanism how mutant results AML remains unclear. NPM1 directly regions hijacks AML-driving genes.</p><p><i><a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-22-0366" target="_blank">See related article Uckelmann et al., p. 746</a>.</i></p><p><a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-13-3-ITI" target="_blank">This highlighted This Issue feature, 517</a></p></div>