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

Details

Serval ID
serval:BIB_93A8CC8D4E0E
Type
Article: article from journal or magazin.
Collection
Publications
Title
Systems medicine dissection of chr1q-amp reveals a novel PBX1-FOXM1 axis for targeted therapy in multiple myeloma.
Journal
Blood
Author(s)
Trasanidis N., Katsarou A., Ponnusamy K., Shen Y.A., Kostopoulos I.V., Bergonia B., Keren K., Reema P., Xiao X., Szydlo R.M., Sabbattini PMR, Roberts IAG, Auner H.W., Naresh K.N., Chaidos A., Wang T.L., Magnani L., Caputo V.S., Karadimitris A.
ISSN
1528-0020 (Electronic)
ISSN-L
0006-4971
Publication state
Published
Issued date
31/03/2022
Peer-reviewed
Oui
Volume
139
Number
13
Pages
1939-1953
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
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.
Keywords
Chromosomes, Human, Pair 1/metabolism, Forkhead Box Protein M1/genetics, Humans, Multiple Myeloma/drug therapy, Multiple Myeloma/genetics, Multiple Myeloma/metabolism, Pre-B-Cell Leukemia Transcription Factor 1/genetics, Prognosis, Systems Analysis, Transcription Factors/genetics
Pubmed
Web of science
Open Access
Yes
Create date
02/12/2024 16:49
Last modification date
04/12/2024 7:07
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