Systems medicine dissection of chr1q-amp reveals a novel PBX1-FOXM1 axis for targeted therapy in multiple myeloma
File(s)
Published version
OA Location
Author(s)
Type
Journal Article
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.
Date Issued
2022-03-31
Date Acceptance
2021-12-20
Citation
Blood, 2022, 139 (13), pp.1939-1953
ISSN
0006-4971
Publisher
American Society of Hematology (ASH Publications)
Start Page
1939
End Page
1953
Journal / Book Title
Blood
Volume
139
Issue
13
Copyright Statement
© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercialNoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.
Identifier
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000783860700008&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=a2bf6146997ec60c407a63945d4e92bb
Subjects
AMPLIFICATION
CHROMOSOME BAND 1Q21
CKS1B
EXPRESSION
GAIN
Hematology
Life Sciences & Biomedicine
OVEREXPRESSION
PROGNOSIS
PROGRESSION
PROLIFERATION
Science & Technology
SURVIVAL
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2022-01-11