Imperial College London
Alternate

ProfessorLucaMagnani

Faculty of Medicine, Department of Surgery & Cancer

Honorary Principal Research Fellow
 
 
 
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Contact

 

+44 (0)20 7594 2808l.magnani CV

 
 
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Location

 

137ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Trasanidis:2021:10.1101/2021.11.17.469031,
author = {Trasanidis, N and Katsarou, A and Ponnusamy, K and Shen, Y-A and Kostopoulos, IV and Bergonia, B and Keren, K and Reema, P and Xiao, X and Szydlo, RM and Sabbattini, PMR and Roberts, IAG and Auner, HW and Naresh, KN and Chaidos, A and Wang, T-L and Magnani, L and Caputo, VS and Karadimitris, A},
doi = {10.1101/2021.11.17.469031},
title = {Systems medicine dissection of chromosome 1q amplification reveals oncogenic regulatory circuits and informs targeted therapy in cancer},
url = {http://dx.doi.org/10.1101/2021.11.17.469031},
year = {2021}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - <jats:title>Abstract</jats:title><jats:p>Understanding the biological and clinical impact of copy number aberrations (CNA) in cancer remains an unmet challenge. Genetic amplification of chromosome 1q (chr1q-amp) is a major CNA conferring adverse prognosis in several cancers, including the blood cancer, multiple myeloma (MM). Although several chr1q genes portend high-risk MM disease, the underpinning molecular aetiology remains elusive. Here we integrate patient multi-omics datasets with genetic variables to identify 103 adverse prognosis genes in chr1q-amp MM. Amongst these, the transcription factor PBX1 is ectopically expressed by genetic amplification and epigenetic activation of its own preserved 3D regulatory domain. By binding to reprogrammed super-enhancers, PBX1 directly regulates critical oncogenic pathways, whilst in co-operation with FOXM1, activates a proliferative gene signature which predicts adverse prognosis across multiple cancers. Notably, pharmacological disruption of the PBX1-FOXM1 axis, including with a novel PBX1 inhibitor is selectively toxic against chr1q-amp cancer 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 cancer.</jats:p><jats:sec><jats:title>Significance</jats:title><jats:p>We provide a comprehensive systems medicine strategy to unveil oncogenic circuitries and inform novel precision therapy decisions against CNA in cancer. This first clinical multi-omic analysis of chr1q-amp in MM identifies a central PBX1-FOXM1 regulatory axis driving high-risk prognosis, as a novel therapeutic target against chr1q-amp in cancer.</jats:p></jats:sec>
AU  - Trasanidis,N
AU  - Katsarou,A
AU  - Ponnusamy,K
AU  - Shen,Y-A
AU  - Kostopoulos,IV
AU  - Bergonia,B
AU  - Keren,K
AU  - Reema,P
AU  - Xiao,X
AU  - Szydlo,RM
AU  - Sabbattini,PMR
AU  - Roberts,IAG
AU  - Auner,HW
AU  - Naresh,KN
AU  - Chaidos,A
AU  - Wang,T-L
AU  - Magnani,L
AU  - Caputo,VS
AU  - Karadimitris,A
DO  - 10.1101/2021.11.17.469031
PY  - 2021///
TI  - Systems medicine dissection of chromosome 1q amplification reveals oncogenic regulatory circuits and informs targeted therapy in cancer
UR  - http://dx.doi.org/10.1101/2021.11.17.469031
ER  -
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