Aberrant activation of RPB1 is critical for cell overgrowth in acute myeloid leukemia.

Abstract

Acute myeloid leukemia (AML) is a group of highly aggressive malignancies with a 5-year overall survival of less than 40%. Cell overgrowth with defective apoptosis is a hallmark of AML, but little is known about how it occurs. Here, we show that aberrant activation of the largest subunit of RNA polymerase II (RPB1) encoded by POLR2A gene is critically involved in this hallmark. We retrospectively analyzed the expression profiles of POLR2A and RPB1 in a panel of AML cell lines, primary AML patients and peripheral blood samples. Meanwhile, correlation analysis was used to explore the correlation between the expression of RPB1 with tumor burden and overall survival time in untreated AML samples. RNA-Seq approach was performed to identify the differentially expressed genes between RPB1 silencing AML cells with control cells after knocking out RPB1. Furthermore, orthotopic AML models were established with RPB1 silencing and control cells to investigate the effects of RPB1 protein level on leukemia cell growth. In most AML patients, RPB1 was aberrantly activated and closely associated with poor prognosis, but not in normal hematopoietic cells. Global transcriptomic analysis revealed that POLR2A knockout strongly impaired growth of AML cells by selectively depleting a substantial set of AML-related oncogenic and anti-apoptosis genes such as MYC, RUNX2, MEIS1, CDC25A and BCL-2. Silencing RPB1 by genetic technology led to a potent regression of human refractory AML in mouse models. These findings reveal that dysregulated RPB1 is a central oncogenic hub that drives overgrowth by hijacking an array of oncogenic and anti-apoptosis factors. Targeting RPB1 is a potential therapeutic for treating AML.

• Authors: Qingfeng Yu, Ying Xu, Haifeng Zhuang, Zhaoxing Wu, Lei Zhang, Jinfan Li, Linlin Yang, Bowen Wu, Ping Wang, Xuzhao Zhang, Xiaoxian Gan, Yun Liang, Shu Zheng, Xiaofang Yu, Ying Gu, Rongzhen Xu
• Journal: Experimental cell research (Exp Cell Res) Vol. 384 Issue 2 Pg. 111653 (11 15 2019) ISSN: 1090-2422 [Electronic] United States
• PMID: 31574286 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Apoptosis Regulatory Proteins
• RNA Polymerase II
• Rpb1 protein, mouse

Topics

• Animals
• Apoptosis (genetics)
• Apoptosis Regulatory Proteins (genetics)
• Cell Line
• Cell Line, Tumor
• Cell Proliferation (genetics)
• Female
• Gene Expression Profiling (methods)
• Gene Expression Regulation, Leukemic (genetics)
• HEK293 Cells
• HL-60 Cells
• Humans
• Leukemia, Myeloid, Acute (genetics, pathology)
• Mice
• RNA Polymerase II (genetics)
• Retrospective Studies
• THP-1 Cells