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Lookup NU author(s): Dr Peixun Zhou, Alex Newman, Filbert Adlar, Casey Broadbent, Dr Alison Blain, Emeritus Professor Andy Hall, Anna Whitehead, Professor ELizabeth Molyneux, Professor Simon BaileyORCiD, Dr Christopher BaconORCiD, Dr Simon BomkenORCiD, Dr Vikki Rand
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Background: Burkitt lymphoma (BL) is an aggressive mature B-cell non-Hodgkin lymphoma (B-NHL) which consists of three subtypes: sporadic BL (sBL), endemic BL(eBL) and immuno-deficiency related BL. Over 90% of children diagnosed with sBL in high-income countries are successfully treated by current high-intensity protocols. However, such intensive regimens are undeliverable in less well-resourced settings. There is a need to identify markers to stratify low- and high-risk patients and identify new therapeutic strategies. We have identified recurrent activating mutations of the transcription factor FOXO1 in both eBL and sBL. Similar mutations have been with poor outcome in diffuse large B cell lymphoma in adults, however the importance of FOXO1 has not been investigated in BL. Objectives: To investigate the prognostic significance and therapeutic potential of the transcription factor FOXO1 in endemic and sporadic BL. Design/methods: 136 patient samples were included in this study; 83 endemic BL cases from the Queen Elizabeth Central Hospital, Malawi and 53 from the Children’s Cancer and Leukaemia Group (CCLG), UK. Diagnosis was confirmed according to World Health Organisation (WHO) 2016 criteria. FOXO1 mutations were detected using next-generation and Sanger sequencing. Six publications were identified and the next-generation sequencing data analysed to investigate the frequency of FOXO1 mutations in BL. Results: FOXO1 non-synonymous mutations were identified in 45/83 (54.2%) of our paediatric endemic BL diagnostic cohort and in 15/53 (28.3%) of the paediatric sporadic BL diagnostic cohort. The frequency of mutations in sporadic BL is significantly higher than mutations identified by our reanalysis of the six published next-generation sequencing datasets, in which we identified mutations in 3/83 (3.6%) cases. Overall, comparison of the frequency of mutations in our endemic BL cohort shows the frequency of FOXO1 mutations is significantly higher than in sporadic BL cohort. The majority of recurrent FOXO1 mutations in this study clustered in the AKT recognition motif (RxRxxS/T) of FOXO1, which potentially leads to dephosphorylation (activation) and nuclear accumulation of FOXO1. The functional impact of AKT motif mutations are being investigated in a panel of CRISPr edited BL cell-lines. Conclusion: We have shown that FOXO1 mutations occur at high frequency in both endemic and sporadic BL but are significantly more common in endemic disease. The mutation hotspot in the AKT recognition motif suggests a potential oncogenic role in paediatric BL.
Author(s): Zhou P, Newman AM, Adlar F, Broadbent C, Blain A, Hall A, Whitehead A, Chagaluka G, Molyneux E, Bailey S, Bacon CM, Bomken S, Rand V
Publication type: Conference Proceedings (inc. Abstract)
Publication status: Published
Conference Name: Sixth International Symposium on Childhood, Adolescent and Young Adult Non-Hodgkin Lymphoma
Year of Conference: 2018
Pages: 51-52
Print publication date: 26/09/2018
Online publication date: 19/09/2018
Acceptance date: 19/09/2018
Date deposited: 24/04/2019
ISSN: 0007-1048
Publisher: John Wiley & Sons Ltd
URL: https://doi.org/10.1111/bjh.15536
DOI: 10.1111/bjh.15536
PubMed id: 30230525
Series Title: British Journal of Haematology
