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C.5 Musashi-1 is a master regulator of aberrant translation in MYC-amplified Group 3 medulloblastoma

Published online by Cambridge University Press:  05 January 2022

MM Kameda-Smith
Affiliation:
(Hamilton)*
H Zhu
Affiliation:
(Toronto)
E Luo
Affiliation:
(San Diego)
C Venugopal
Affiliation:
(Hamilton)
K Brown
Affiliation:
(Toronto)
BA Yee
Affiliation:
(San Diego)
S Xing
Affiliation:
(Hamilton)
F Tan
Affiliation:
(San Diego)
D Bakhshinyan
Affiliation:
(Hamilton)
AA Adile
Affiliation:
(Hamilton)
M Subapanditha
Affiliation:
(Hamilton)
D Picard
Affiliation:
(Dusseldorf)
J Moffat
Affiliation:
(Toronto)
A Fleming
Affiliation:
(Hamilton)
K Hope
Affiliation:
(Hamilton)
J Provias
Affiliation:
(Hamilton)
M Remke
Affiliation:
(Dusseldorf)
Y Lu
Affiliation:
(Hamilton)
J Reimand
Affiliation:
(Toronto)
R Wechsler-Reya
Affiliation:
(La Jolla)
G Yeo
Affiliation:
(San Diego)
SK Singh
Affiliation:
(Hamilton)
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Abstract

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Background: Medulloblastoma (MB) is the most common solid malignant pediatric brain neoplasm. Group 3 (G3) MB, particularly MYC amplified G3 MB, is the most aggressive subgroup with the highest frequency of children presenting with metastatic disease, and is associated with a poor prognosis. To further our understanding of the role of MSI1 in MYC amplified G3 MB, we performed an unbiased integrative analysis of eCLIP binding sites, with changes observed at the transcriptome, the translatome, and the proteome after shMSI1 inhibition. Methods: Primary human pediatric MBs, SU_MB002 and HD-MB03 were kind gifts from Dr. Yoon-Jae Cho (Harvard, MS) and Dr. Till Milde (Heidelberg) and cultured for in vitro and in vivo experiments. eCLIP, RNA-seq, Polysome-seq, and TMT-MS were completed as previously described. Results:MSI1 is overexpressed in G3 MB. shRNA Msi1 interference resulted in a reduction in tumour burden conferring a survival advantage to mice injected with shMSI1 G3MB cells. Robust ranked multiomic analysis (RRA) identified an unconventional gene set directly perturbed by MSI1 in G3 MB. Conclusions: Our robust unbiased integrative analysis revealed a distinct role for MSI1 in the maintenance of the stem cell state in G3 MB through post-transcriptional modification of multiple pathways including identification of unconventional targets such as HIPK1.

Type
Platform Presentations
Copyright
© The Author(s), 2021. Published by Cambridge University Press on behalf of Canadian Neurological Sciences Federation