A somatic UBA2 variant preceded ETV6-RUNX1 in the concordant BCP-ALL of monozygotic twins.
Chromosome Aberrations
Core Binding Factor Alpha 2 Subunit
/ genetics
Humans
Infant, Newborn
Oncogene Proteins, Fusion
/ genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma
/ diagnosis
Proto-Oncogene Proteins c-ets
/ genetics
Repressor Proteins
/ genetics
Twins, Monozygotic
/ genetics
Ubiquitin-Activating Enzymes
/ genetics
ETS Translocation Variant 6 Protein
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
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
2275-2289Informations 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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