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dc.contributor.authorNikolaev, Sergey I.en
dc.contributor.authorGarieri, Marcoen
dc.contributor.authorSantoni, Federicoen
dc.contributor.authorFalconnet, Emilieen
dc.contributor.authorRibaux, Pascaleen
dc.contributor.authorGuipponi, Michelen
dc.contributor.authorMurray, Aoifeen
dc.contributor.authorGroet, Jürgenen
dc.contributor.authorGiarin, Emanuelaen
dc.contributor.authorBasso, Giuseppeen
dc.contributor.authorNizetic, Deanen
dc.contributor.authorAntonarakis, Stylianos E.en
dc.identifier.citationNikolaev, S. I., Garieri, M., Santoni, F., Falconnet, E., Ribaux, P., Guipponi, M., et al. (2014). Frequent cases of RAS-mutated down syndrome acute lymphoblastic leukaemia lack JAK2 mutations. Nature communications, 5.en
dc.description.abstractChildren with Down syndrome (DS) and acute lymphoblastic leukaemia (ALL) have poorer survival and more relapses than non-DS children with ALL, highlighting an urgent need for deeper mechanistic understanding of DS–ALL. Here, using full-exome or cancer genes-targeted sequencing of 42 ALL samples from 39 DS patients, we uncover driver mutations in RAS, (​KRAS and ​NRAS) recurring to a similar extent (15/42) as ​JAK2 (12/42) mutations or ​P2RY8-​CRLF2 fusions (14/42). RAS mutations are almost completely mutually exclusive with ​JAK2 mutations (P=0.016), driving a combined total of two-thirds of analysed cases. Clonal architecture analysis reveals that both RAS and ​JAK2 drove sub-clonal expansions primarily initiated by ​CRLF2 rearrangements, and/or mutations in chromatin remodellers and lymphocyte differentiation factors. Remarkably, in 2/3 relapsed cases, there is a switch from a primary ​JAK2- or ​PTPN11-mutated sub-clone to a RAS-mutated sub-clone in relapse. These results provide important new insights informing the patient stratification strategies for targeted therapeutic approaches for DS–ALL.en
dc.format.extent23 p.en
dc.relation.ispartofseriesNature communicationsen
dc.rights© 2014 Macmillan Publishers Ltd. This is the author created version of a work that has been peer reviewed and accepted for publication in Nature Communications, published by Nature Publishing Group on behalf of Macmillan Publishers Ltd. It incorporates referee’s comments but changes resulting from the publishing process, such as copyediting, structural formatting, may not be reflected in this document. The published version is available at: [Article DOI:].en
dc.subjectDRNTU::Science::Biological sciences::Human anatomy and physiologyen
dc.titleFrequent cases of RAS-mutated down syndrome acute lymphoblastic leukaemia lack JAK2 mutationsen
dc.typeJournal Articleen
dc.contributor.schoolLee Kong Chian School of Medicine (LKCMedicine)en
dc.description.versionAccepted versionen
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