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A somatic UBA2 vari...
A somatic UBA2 variant preceded ETV6-RUNX1 in the concordant BCP-ALL of monozygotic twins
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- Bang, Benedicte (författare)
- Karolinska Institutet
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- Eisfeldt, Jesper (författare)
- Karolinska Institutet
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- Barbany, Gisela (författare)
- Karolinska Institutet
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- Harila-Saari, Arja H. (författare)
- Uppsala universitet,Barnonkologisk och neurologisk forskning
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- Heyman, Mats (författare)
- Karolinska Institutet
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- Zachariadis, Vasilios (författare)
- Karolinska Inst, Canc Ctr Karolinska CCK, Dept Oncol Pathol, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden.
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- Taylan, Fulya (författare)
- Karolinska Institutet
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- Nordgren, Ann (författare)
- Karolinska Institutet
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(creator_code:org_t)
- 2022-04-04
- 2022
- Engelska.
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 6:7, s. 2275-2289
- Relaterad länk:
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https://ashpublicati...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Hematologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Hematology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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