Systems medicine dissection of chr1q-amp reveals a novel PBX1-FOXM1 axis for targeted therapy in multiple myeloma.

Abstract

Understanding the biological and clinical impact of copy number aberrations (CNAs) on the development of precision therapies in cancer remains an unmet challenge. Genetic amplification of chromosome 1q (chr1q-amp) is a major CNA conferring an adverse prognosis in several types of cancer, including in the blood cancer multiple myeloma (MM). Although several genes across chromosome 1 (chr1q) portend high-risk MM disease, the underpinning molecular etiology remains elusive. Here, with reference to the 3-dimensional (3D) chromatin structure, we integrate multi-omics data sets from patients with MM with genetic variables to obtain an associated clinical risk map across chr1q and to identify 103 adverse prognosis genes in chr1q-amp MM. Prominent among these genes, the transcription factor PBX1 is ectopically expressed by genetic amplification and epigenetic activation of its own preserved 3D regulatory domain. By binding to reprogrammed superenhancers, PBX1 directly regulates critical oncogenic pathways and a FOXM1-dependent transcriptional program. Together, PBX1 and FOXM1 activate a proliferative gene signature that predicts adverse prognosis across multiple types of cancer. Notably, pharmacological disruption of the PBX1-FOXM1 axis with existing agents (thiostrepton) and a novel PBX1 small molecule inhibitor (T417) is selectively toxic against chr1q-amp myeloma and solid tumor cells. Overall, our systems medicine approach successfully identifies CNA-driven oncogenic circuitries, links them to clinical phenotypes, and proposes novel CNA-targeted therapy strategies in MM and other types of cancer.

• Authors: Nikolaos Trasanidis, Alexia Katsarou, Kanagaraju Ponnusamy, Yao-An Shen, Ioannis V Kostopoulos, Bien Bergonia, Keren Keren, Paudel Reema, Xiaolin Xiao, Richard M Szydlo, Pierangela M R Sabbattini, Irene A G Roberts, Holger W Auner, Kikkeri N Naresh, Aristeidis Chaidos, Tian-Li Wang, Luca Magnani, Valentina S Caputo, Anastasios Karadimitris
• Journal: Blood (Blood) Vol. 139 Issue 13 Pg. 1939-1953 (03 31 2022) ISSN: 1528-0020 [Electronic] United States
• PMID: 35015835 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Chemical References

• FOXM1 protein, human
• Forkhead Box Protein M1
• Pre-B-Cell Leukemia Transcription Factor 1
• Transcription Factors
• pbx1 protein, human

Topics

• Chromosomes, Human, Pair 1 (metabolism)
• Forkhead Box Protein M1 (genetics)
• Humans
• Multiple Myeloma (drug therapy, genetics, metabolism)
• Pre-B-Cell Leukemia Transcription Factor 1 (genetics)
• Prognosis
• Systems Analysis
• Transcription Factors (genetics)