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Title: | Frequent cases of RAS-mutated down syndrome acute lymphoblastic leukaemia lack JAK2 mutations | Authors: | Nikolaev, Sergey I. Garieri, Marco Santoni, Federico Falconnet, Emilie Ribaux, Pascale Guipponi, Michel Murray, Aoife Groet, Jürgen Giarin, Emanuela Basso, Giuseppe Nizetic, Dean Antonarakis, Stylianos E. |
Keywords: | DRNTU::Science::Biological sciences::Human anatomy and physiology | Issue Date: | 2014 | Source: | Nikolaev, 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. | Series/Report no.: | Nature communications | Abstract: | Children 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. | URI: | https://hdl.handle.net/10356/101511 http://hdl.handle.net/10220/24153 |
ISSN: | 2041-1723 | DOI: | 10.1038/ncomms5654 | Schools: | Lee Kong Chian School of Medicine (LKCMedicine) | 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: http://dx.doi.org/10.1038/ncomms5654]. | Fulltext Permission: | open | Fulltext Availability: | With Fulltext |
Appears in Collections: | LKCMedicine Journal Articles |
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Frequent cases of RAS-mutated Down syndrome acute lymphoblastic leukaemia lack JAK2 mutations.pdf | Main article | 1.31 MB | Adobe PDF | View/Open |
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