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Frequent cases of RAS-mutated Down syndrome acute lymphoblastic leukaemia lack JAK2 mutations

Author

Listed:
  • Sergey I. Nikolaev

    (University of Geneva Medical School, 1 rue Michel Servet, Geneva 1211, Switzerland)

  • Marco Garieri

    (University of Geneva Medical School, 1 rue Michel Servet, Geneva 1211, Switzerland)

  • Federico Santoni

    (University of Geneva Medical School, 1 rue Michel Servet, Geneva 1211, Switzerland
    Geneva University Hospitals—HUG, Service of Genetic Medicine, 4 Rue Gabrielle-Perret-Gentil, Geneva 1211, Switzerland)

  • Emilie Falconnet

    (University of Geneva Medical School, 1 rue Michel Servet, Geneva 1211, Switzerland)

  • Pascale Ribaux

    (University of Geneva Medical School, 1 rue Michel Servet, Geneva 1211, Switzerland)

  • Michel Guipponi

    (Geneva University Hospitals—HUG, Service of Genetic Medicine, 4 Rue Gabrielle-Perret-Gentil, Geneva 1211, Switzerland)

  • Aoife Murray

    (The Blizard Institute, Barts and The London School of Medicine, Queen Mary University of London
    LonDownS Consortium, The Wellcome Trust)

  • Jürgen Groet

    (The Blizard Institute, Barts and The London School of Medicine, Queen Mary University of London
    LonDownS Consortium, The Wellcome Trust)

  • Emanuela Giarin

    (University of Padua, IRP—Istituto di Ricerca Pediatrica—Fondazione Città della Speranza)

  • Giuseppe Basso

    (University of Padua, IRP—Istituto di Ricerca Pediatrica—Fondazione Città della Speranza)

  • Dean Nizetic

    (The Blizard Institute, Barts and The London School of Medicine, Queen Mary University of London
    LonDownS Consortium, The Wellcome Trust
    Lee Kong Chian School of Medicine, Nanyang Technological University, Unit 04-11, Proteos Building, 61 Biopolis Drive, Singapore 138673, Singapore)

  • Stylianos E. Antonarakis

    (University of Geneva Medical School, 1 rue Michel Servet, Geneva 1211, Switzerland
    IGE3 institute of Genetics and Genomics of Geneva, 1 rue Michel Servet, Geneva 1211, Switzerland)

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.

Suggested Citation

  • Sergey I. Nikolaev & Marco Garieri & Federico Santoni & Emilie Falconnet & Pascale Ribaux & Michel Guipponi & Aoife Murray & Jürgen Groet & Emanuela Giarin & Giuseppe Basso & Dean Nizetic & Stylianos , 2014. "Frequent cases of RAS-mutated Down syndrome acute lymphoblastic leukaemia lack JAK2 mutations," Nature Communications, Nature, vol. 5(1), pages 1-6, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5654
    DOI: 10.1038/ncomms5654
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