TY - JOUR
T1 - Systems medicine dissection of chr1q-amp reveals a novel PBX1-FOXM1 axis for targeted therapy in multiple myeloma
AU - Trasanidis, Nikolaos
AU - Katsarou, Alexia
AU - Ponnusamy, Kanagaraju
AU - Shen, Yao An
AU - Kostopoulos, Ioannis V.
AU - Bergonia, Bien
AU - Keren, Keren
AU - Reema, Paudel
AU - Xiao, Xiaolin
AU - Szydlo, Richard M.
AU - Sabbattini, Pierangela M.R.
AU - Roberts, Irene A.G.
AU - Auner, Holger W.
AU - Naresh, Kikkeri N.
AU - Chaidos, Aristeidis
AU - Wang, Tian Li
AU - Magnani, Luca
AU - Caputo, Valentina S.
AU - Karadimitris, Anastasios
N1 - Funding Information:
N.T., V.S.C., X.X., and K.P. were supported by Bloodwise (Blood Cancer UK), and A. Katsarou was supported by the Kay Kendall Leukaemia Fund and the Imperial NIHR Biomedical Research Centre. The authors also acknowledge support from the LMS/NIHR Flow Cytometry Facility, the Imperial NIHR Biomedical Research Centre Genomics Facility, the Imperial NIHR Biomedical Research Centre, and the Cancer Research UK Experimental Cancer Medicine Centre.
Funding Information:
The authors thank Ichiro Hanamura (Aichi Medical University, Nagakute, Aichi, Japan) for providing the NCU.MM1 myeloma cell line, Sadaf Ghaem-Maghami (Imperial College London) for providing the OVCAR3 and A2780 cell lines, and Udayakumar Achandira (Hammersmith Hospital) for advice and assistance with MMCL FISH analysis. N.T. V.S.C. X.X. and K.P. were supported by Bloodwise (Blood Cancer UK), and A. Katsarou was supported by the Kay Kendall Leukaemia Fund and the Imperial NIHR Biomedical Research Centre. The authors also acknowledge support from the LMS/NIHR Flow Cytometry Facility, the Imperial NIHR Biomedical Research Centre Genomics Facility, the Imperial NIHR Biomedical Research Centre, and the Cancer Research UK Experimental Cancer Medicine Centre.
Publisher Copyright:
© 2022 American Society of Hematology
PY - 2022/3/31
Y1 - 2022/3/31
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85127169927&partnerID=8YFLogxK
U2 - 10.1182/blood.2021014391
DO - 10.1182/blood.2021014391
M3 - Article
C2 - 35015835
AN - SCOPUS:85127169927
SN - 0006-4971
VL - 139
SP - 1939
EP - 1953
JO - Blood
JF - Blood
IS - 13
ER -
