Imperial College London
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ProfessorMichaelJohnson

Faculty of Medicine, Department of Brain Sciences

Professor of Neurology and Genomic Medicine
 
 
 
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Contact

 

m.johnson Website

 
 
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Location

 

E419Burlington DanesHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Laaniste:2019:10.1002/acn3.50850,
author = {Laaniste, L and Srivastava, P and Stylianou, T and Syed, N and Cases-Cunillera, S and Shkura, K and Zeng, Q and Rackham, O and Langley, S and Delahaye-Duriez, A and O'Neill, K and Williams, M and Becker, A and Roncaroli, F and Petretto, E and Johnson, M},
doi = {10.1002/acn3.50850},
journal = {Annals of Clinical and Translational Neurology},
pages = {1616--1638},
title = {Integrated systems-genetic analyses reveal a network target for delaying glioma progression},
url = {http://dx.doi.org/10.1002/acn3.50850},
volume = {6},
year = {2019}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - ObjectiveTo identify a convergent, multitarget proliferation characteristic for astrocytoma transformation that could be targeted for therapy discovery.MethodsUsing an integrated functional genomics approach, we prioritized networks associated with astrocytoma progression using the following criteria: differential coexpression between grade II and grade III IDH1mutated and 1p/19q euploid astrocytomas, preferential enrichment for genetic risk to cancer, association with patient survival and samplelevel genomic features. Drugs targeting the identified multitarget network characteristic for astrocytoma transformation were computationally predicted using drug transcriptional perturbation data and validated using primary human astrocytoma cells.ResultsA single network, M2, consisting of 177 genes, was associated with glioma progression on the basis of the above criteria. Functionally, M2 encoded physically interacting proteins regulating cell cycle processes and analysis of genomewide generegulatory interactions using mutual information and DNA–protein interactions revealed the known regulators of cell cycle processes FoxM1, BMyb, and E2F2 as key regulators of M2. These results suggest functional disruption of M2 via gene mutation or altered expression as a convergent pathway regulating astrocytoma transformation. By considering M2 as a multitarget drug target regulating astrocytoma transformation, we identified several drugs that are predicted to restore M2 expression in anaplastic astrocytoma toward its lowgrade profile and of these, we validated the known antiproliferative drug resveratrol as downregulating multiple nodes of M2 including at nanomolar concentrations achievable in human cerebrospinal fluid by oral dosing.InterpretationOur results identify M2 as a multitarget network characteristic for astrocytoma progression and encourage M2based drug screening to identify new compounds for preventing glioma transformation.
AU  - Laaniste,L
AU  - Srivastava,P
AU  - Stylianou,T
AU  - Syed,N
AU  - Cases-Cunillera,S
AU  - Shkura,K
AU  - Zeng,Q
AU  - Rackham,O
AU  - Langley,S
AU  - Delahaye-Duriez,A
AU  - O'Neill,K
AU  - Williams,M
AU  - Becker,A
AU  - Roncaroli,F
AU  - Petretto,E
AU  - Johnson,M
DO  - 10.1002/acn3.50850
EP  - 1638
PY  - 2019///
SN  - 2328-9503
SP  - 1616
TI  - Integrated systems-genetic analyses reveal a network target for delaying glioma progression
T2  - Annals of Clinical and Translational Neurology
UR  - http://dx.doi.org/10.1002/acn3.50850
UR  - http://hdl.handle.net/10044/1/71755
VL  - 6
ER  -
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