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A somatic UBA2 vari...
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Bang, BenedicteKarolinska Institutet
(författare)
A somatic UBA2 variant preceded ETV6-RUNX1 in the concordant BCP-ALL of monozygotic twins
- Artikel/kapitelEngelska2022
Förlag, utgivningsår, omfång ...
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2022-04-04
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American Society of Hematology,2022
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printrdacarrier
Nummerbeteckningar
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LIBRIS-ID:oai:DiVA.org:uu-475178
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-475178URI
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https://doi.org/10.1182/bloodadvances.2021005703DOI
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http://kipublications.ki.se/Default.aspx?queryparsed=id:149467760URI
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Språk:engelska
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Sammanfattning på:engelska
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Ämneskategori:ref swepub-contenttype
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Ämneskategori:art swepub-publicationtype
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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 och genrebeteckningar
Biuppslag (personer, institutioner, konferenser, titlar ...)
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Eisfeldt, JesperKarolinska Institutet
(författare)
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Barbany, GiselaKarolinska Institutet
(författare)
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Harila-Saari, Arja H.Uppsala universitet,Barnonkologisk och neurologisk forskning(Swepub:uu)arjha456
(författare)
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Heyman, MatsKarolinska Institutet
(författare)
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Zachariadis, VasiliosKarolinska Inst, Canc Ctr Karolinska CCK, Dept Oncol Pathol, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden.
(författare)
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Taylan, FulyaKarolinska Institutet
(författare)
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Nordgren, AnnKarolinska Institutet
(författare)
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Karolinska InstitutetBarnonkologisk och neurologisk forskning
(creator_code:org_t)
Sammanhörande titlar
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Ingår i:Blood Advances: American Society of Hematology6:7, s. 2275-22892473-95292473-9537
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