A somatic UBA2 variant preceded ETV6-RUNX1 in the concordant BCP-ALL of monozygotic twins.


Journal

Blood advances
ISSN: 2473-9537
Titre abrégé: Blood Adv
Pays: United States
ID NLM: 101698425

Informations de publication

Date de publication:
12 04 2022
Historique:
received: 06 07 2021
accepted: 06 12 2021
pubmed: 5 1 2022
medline: 7 4 2022
entrez: 4 1 2022
Statut: ppublish

Résumé

Genetic analysis of leukemic clones in monozygotic twins with concordant acute lymphoblastic leukemia (ALL) has proved a unique opportunity to gain insight into the molecular phylogenetics of leukemogenesis. Using whole-genome sequencing, we characterized constitutional and somatic single nucleotide variants/insertion-deletions (indels) and structural variants in a monozygotic twin pair with concordant ETV6-RUNX1+ B-cell precursor ALL (BCP-ALL). In addition, digital PCR (dPCR) was applied to evaluate the presence of and quantify selected somatic variants at birth, diagnosis, and remission. A shared somatic complex rearrangement involving chromosomes 11, 12, and 21 with identical fusion sequences in leukemias of both twins offered direct proof of a common clonal origin. The ETV6-RUNX1 fusion detected at diagnosis was found to originate from this complex rearrangement. A shared somatic frameshift deletion in UBA2 was also identified in diagnostic samples. In addition, each leukemia independently acquired analogous deletions of 3 genes recurrently targeted in BCP-ALLs (ETV6, ATF7IP, and RAG1/RAG2), providing evidence of a convergent clonal evolution only explained by a strong concurrent selective pressure. Quantification of the UBA2 deletion by dPCR surprisingly indicated it persisted in remission. This, for the first time to our knowledge, provided evidence of a UBA2 variant preceding the well-established initiating event ETV6-RUNX1. Further, we suggest the UBA2 deletion exerted a leukemia predisposing effect and that its essential role in Small Ubiquitin-like Modifier (SUMO) attachment (SUMOylation), regulating nearly all physiological and pathological cellular processes such as DNA-repair by nonhomologous end joining, may hold a mechanistic explanation for the predisposition.

Identifiants

pubmed: 34982829
pii: 483331
doi: 10.1182/bloodadvances.2021005703
pmc: PMC9006272
doi:

Substances chimiques

Core Binding Factor Alpha 2 Subunit 0
Oncogene Proteins, Fusion 0
Proto-Oncogene Proteins c-ets 0
RUNX1 protein, human 0
Repressor Proteins 0
UBA2 protein, human 0
Ubiquitin-Activating Enzymes EC 6.2.1.45

Types de publication

Case Reports Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

2275-2289

Informations de copyright

© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

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Auteurs

Benedicte Bang (B)

Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.

Jesper Eisfeldt (J)

Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.

Gisela Barbany (G)

Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.

Arja Harila-Saari (A)

Department of Women's and Children's Health, Uppsala University Hospital, Uppsala, Sweden.

Mats Heyman (M)

Department of Women's and Children's Health, Karolinska University Hospital Solna, Stockholm, Sweden; and.

Vasilios Zachariadis (V)

Department of Oncology-Pathology, Cancer Centre Karolinska (CCK), Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden.

Fulya Taylan (F)

Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.

Ann Nordgren (A)

Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.

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