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Identification of Burkitt lymphoma vulnerabilities using RNAi

Hüllein, Jennifer

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Oncogenic activation of MYC drives cell proliferation in Burkitt lymphoma (BL), but also evokes stress signals that have to be counterbalanced to escape apoptosis. Pro-survival signals from tonic B cell receptor and PI3K signaling are essential, but additional mutations are required for malignant transformation. TP53 mutations were identified in 43% of BL patients. Mutations in the conserved MYC box I that abrogate activation of pro-apoptotic Bcl2-family member Bim were present in 17% of BL patients. Notably, MYC box I and TP53 mutations occurred independently and accounted for 54% of cases, suggesting that alternative failsafe mechanisms may be inactivated in BL. To study alternative mechanisms of transformation in the absence of TP53 mutations, we analyzed the pattern of recurrent genetic aberrations in BL for associations with TP53 status. We observed an overrepresentation of chromosome 1q gains in TP53 wild-type BL patients, which was not observed in diffuse large B cell lymphoma (DLBCL) patients. Minimally gained regions comprised 1q21-q23 and 1q32 and amplified regions displayed a gene dosage effect as shown by gene expression analysis. To identify genes essential for p53 wild-type BL cells we performed a RNAi loss-of-function screen in a panel of genetically defined cell lines. We used a pooled shRNA library targeting 5,000 genes in key signaling pathways across the genome. Our data was probed against published RNAi screens across cancer entities and showed a high overlap of common essential and non-essential genes. p53 wild-type BL cell lines showed a strong and specific dependence on the p53 inhibitor MDM4. Depletion of MDM4 resulted in an upregulation of p53 target genes and induced cell cycle arrest. In a mouse xenograft model, MDM4 knock-down significantly reduced tumor growth. These effects were p53 dependent as confirmed in an isogenic p53 knock-out cell line. MDM4 is located within the minimally gained region 1q32 associated with p53 wild-type BL patients and might therefore contribute to BL pathogenesis by inactivation of the p53 pathway. Our data suggest that reactivation of p53 in patients lacking TP53 mutation, e.g. by specific MDM4 inhibition, is a promising therapeutic approach. Re-analysis of published RNAi screening data revealed p53-specific sensitivity of MDM4 knock-down across cancer cell lines, suggesting a broader application for MDM4 inhibitors. Our data set on essential genes in Burkitt lymphoma proved to be a valuable resource for identification of genotype-specific vulnerabilities. This analysis could be extended by integration of published RNAi screening data in non-lymphoid cell lines to identify interesting potential entity-specific vulnerabilities.

Item Type: Dissertation
Supervisor: Kalle, Prof. Dr. Christof von
Place of Publication: Heidelberg
Date of thesis defense: 30 June 2016
Date Deposited: 25 Aug 2016 08:06
Date: 2017
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 500 Natural sciences and mathematics
570 Life sciences
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