Challenging our understanding of B‐cell lymphomagenesis and risk: Paediatric high‐grade B‐cell lymphoma, not otherwise specified with a <i>DDX3X::MLLT10</i> fusion and an <i>IGH</i> deletion

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Abstract

We report a unique case of high‐grade B‐cell lymphoma, not otherwise specified in a 5‐year‐old child. Whole‐genome sequencing revealed a DDX3X::MLLT10 fusion, usually seen in T‐cell acute lymphoblastic leukaemia (ALL). This suggests the novel idea that MLLT10 fusions are capable of driving B‐cell malignancies. An IGH deletion usually only seen in adults was also found. These unique genetic findings provide novel insights into B‐cell lymphomagenesis. The child remains in remission 7 year post chemotherapy, which demonstrates that novel complex molecular findings do not always denote high‐risk disease.

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Most cited references 28

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COSMIC: the Catalogue Of Somatic Mutations In Cancer

John G Tate, Sally Bamford, Harry C Jubb … (2018)

Abstract COSMIC, the Catalogue Of Somatic Mutations In Cancer (https://cancer.sanger.ac.uk) is the most detailed and comprehensive resource for exploring the effect of somatic mutations in human cancer. The latest release, COSMIC v86 (August 2018), includes almost 6 million coding mutations across 1.4 million tumour samples, curated from over 26 000 publications. In addition to coding mutations, COSMIC covers all the genetic mechanisms by which somatic mutations promote cancer, including non-coding mutations, gene fusions, copy-number variants and drug-resistance mutations. COSMIC is primarily hand-curated, ensuring quality, accuracy and descriptive data capture. Building on our manual curation processes, we are introducing new initiatives that allow us to prioritize key genes and diseases, and to react more quickly and comprehensively to new findings in the literature. Alongside improvements to the public website and data-download systems, new functionality in COSMIC-3D allows exploration of mutations within three-dimensional protein structures, their protein structural and functional impacts, and implications for druggability. In parallel with COSMIC’s deep and broad variant coverage, the Cancer Gene Census (CGC) describes a curated catalogue of genes driving every form of human cancer. Currently describing 719 genes, the CGC has recently introduced functional descriptions of how each gene drives disease, summarized into the 10 cancer Hallmarks.

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The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms

Rita Alaggio, Catalina Amador, Ioannis Anagnostopoulos … (2022)

We herein present an overview of the upcoming 5th edition of the World Health Organization Classification of Haematolymphoid Tumours focussing on lymphoid neoplasms. Myeloid and histiocytic neoplasms will be presented in a separate accompanying article. Besides listing the entities of the classification, we highlight and explain changes from the revised 4th edition. These include reorganization of entities by a hierarchical system as is adopted throughout the 5th edition of the WHO classification of tumours of all organ systems, modification of nomenclature for some entities, revision of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities, as well as inclusion of tumour-like lesions, mesenchymal lesions specific to lymph node and spleen, and germline predisposition syndromes associated with the lymphoid neoplasms.

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The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development.

Ana Ortega-Molina, Isaac Boss, Andrés Canela … (2015)

The gene encoding the lysine-specific histone methyltransferase KMT2D has emerged as one of the most frequently mutated genes in follicular lymphoma and diffuse large B cell lymphoma; however, the biological consequences of KMT2D mutations on lymphoma development are not known. Here we show that KMT2D functions as a bona fide tumor suppressor and that its genetic ablation in B cells promotes lymphoma development in mice. KMT2D deficiency also delays germinal center involution and impedes B cell differentiation and class switch recombination. Integrative genomic analyses indicate that KMT2D affects methylation of lysine 4 on histone H3 (H3K4) and expression of a set of genes, including those in the CD40, JAK-STAT, Toll-like receptor and B cell receptor signaling pathways. Notably, other KMT2D target genes include frequently mutated tumor suppressor genes such as TNFAIP3, SOCS3 and TNFRSF14. Therefore, KMT2D mutations may promote malignant outgrowth by perturbing the expression of tumor suppressor genes that control B cell-activating pathways.

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Author and article information

Contributors

G. A. Amos Burke: amos.burke@nhs.net

Journal

Journal ID (nlm-ta): Pediatr Blood Cancer

Journal ID (iso-abbrev): Pediatr Blood Cancer

Journal ID (doi): 10.1002/(ISSN)1545-5017

Journal ID (publisher-id): PBC

Title: Pediatric Blood & Cancer

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Print): 1545-5009

ISSN (Electronic): 1545-5017

Publication date (Electronic): 16 December 2023

Publication date (Print): March 2024

Volume: 71

Issue: 3 ( doiID: 10.1002/pbc.v71.3 )

Electronic Location Identifier: e30810

Affiliations

[ ¹ ] Department of Pathology University of Cambridge Cambridge UK

[ ² ] Department of Paediatric Haematology, Oncology and Palliative Care Addenbrooke's Hospital Cambridge UK

[ ³ ] East‐Genomics Laboratory Hub (GLH) Genetics Laboratory Cambridge University Hospitals NHS Foundation Trust Cambridge UK

[ ⁴ ] Department of Pathology Addenbrooke's Hospital Cambridge UK

Author notes

[*] [* ] Correspondence

G. A. Amos Burke, Department of Paediatric Haematology, Oncology and Palliative Care, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.

Email: amos.burke@ 123456nhs.net

Author information

Lucy Hare https://orcid.org/0000-0001-8159-6165

Jamie Trotman https://orcid.org/0000-0002-6246-4121

Article

Publisher ID: PBC30810

DOI: 10.1002/pbc.30810

PMC ID: 11497301

PubMed ID: 38102963

SO-VID: 806f7aaa-0a22-42e6-ae10-3e2841d98cfd

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

History

Date revision received : 26 November 2023

Date received : 12 August 2023

Date accepted : 28 November 2023

Page count

Figures: 2, Tables: 0, Pages: 5, Words: 3142

Funding

Funded by: Cancer Research UK Cambridge Centre clinical research fellowship

Award ID: C9685/A25117

Custom metadata

source-schema-version-number 2.0

cover-date March 2024

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:6.4.9 mode:remove_FC converted:23.10.2024

ScienceOpen disciplines: Pediatrics

Keywords: hgbl,lymphoma,mllt10,nos

Data availability:

ScienceOpen disciplines: Pediatrics

Keywords: hgbl, lymphoma, mllt10, nos

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Challenging our understanding of B‐cell lymphomagenesis and risk: Paediatric high‐grade B‐cell lymphoma, not otherwise specified with a DDX3X::MLLT10 fusion and an IGH deletion

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Pediatric Pulse: Advancing Neonatal and Child Health

Most cited references 28

COSMIC: the Catalogue Of Somatic Mutations In Cancer

The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms

The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development.

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