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Sporadic and endemic Burkitt lymphoma have frequent FOXO1 mutations but distinct hotspots in the AKT recognition motif

Lookup NU author(s): Dr Peixun Zhou, Alex Blain, Alex Newman, Dr Masood Zaka, Dr Ugo Offor, Lewis Chaytor, Anna Whitehead, Emeritus Professor Andy Hall, Professor Simon Bailey, Professor ELizabeth Molyneux, Dr Christopher Bacon, Dr Simon Bomken, Dr Vikki Rand

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

FOXO1 has an oncogenic role in adult germinal center derived lymphomas, in which mutations, predominately within the AKT recognition motif, cause nuclear retention of FOXO1 resulting in increased cell proliferation. To determine the prevalence and distribution of FOXO1 mutations in pediatric Burkitt lymphoma (BL), we sequenced a large number of sporadic and endemic BL patient samples. We report a high frequency of FOXO1 mutations in both sporadic and endemic BL at diagnosis, occurring in 23/78 (29%) and 48/89 (54%) samples respectively, as well as 8/16 (50%) cases at relapse. Mutations of T24 were the most common in sporadic BL but were rare in endemic cases, in which mutations of residue S22, also within the AKT recognition motif, were the most frequent. FOXO1 mutations were almost always present in the major tumor cell clone but were not associated with outcome. Analysis of other recurrent mutations reported in BL revealed that FOXO1 mutations were associated with mutations of DDX3X and ARID1A, but not MYC, TCF3/ID3 or members of the phosphatidylinositol 3’ OH kinase (PI3K) signaling pathway. We further show common nuclear retention of the FOXO1 protein, irrespective of mutation status, suggesting alternative unknown mechanisms for maintaining FOXO1 transcriptional activity in BL. CRISPR/Cas9 knockout of FOXO1 in an endemic cell line produced a significant decrease in cell proliferation, supporting an oncogenic role for FOXO1 in endemic BL. Thus, FOXO1 is frequently mutated in both sporadic and endemic BL and may offer a potential therapeutic target for pediatric BL patients worldwide.


Publication metadata

Author(s): Zhou P, Blain AE, Newman AM, Zaka M, Chagaluka G, Adlar F, Offor UT, Broadbent C, Chaytor L, Whitehead A, Hall A, O'Connor H, Van Noorden S, Lampert I, Bailey S, Molyneux E, Bacon CM, Bomken S, Rand V

Publication type: Article

Publication status: Published

Journal: Blood Advances

Year: 2019

Volume: 3

Issue: 14

Pages: 2118-2127

Online publication date: 12/07/2019

Acceptance date: 14/04/2019

Date deposited: 29/08/2019

ISSN (print): 2473-9529

ISSN (electronic): 2473-9537

Publisher: American Society of Hematology

URL: https://doi.org/10.1182/bloodadvances.2018029546

DOI: 10.1182/bloodadvances.2018029546


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