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

  • Nikolaev SI 1] Department of Genetic Medicine and Development, University of Geneva Medical School, 1 rue Michel Servet, Geneva 1211, Switzerland [2].
  • Garieri M Department of Genetic Medicine and Development, University of Geneva Medical School, 1 rue Michel Servet, Geneva 1211, Switzerland.
  • Santoni F 1] Department of Genetic Medicine and Development, University of Geneva Medical School, 1 rue Michel Servet, Geneva 1211, Switzerland [2] Geneva University Hospitals-HUG, Service of Genetic Medicine, 4 Rue Gabrielle-Perret-Gentil, Geneva 1211, Switzerland.
  • Falconnet E Department of Genetic Medicine and Development, University of Geneva Medical School, 1 rue Michel Servet, Geneva 1211, Switzerland.
  • Ribaux P Department of Genetic Medicine and Development, University of Geneva Medical School, 1 rue Michel Servet, Geneva 1211, Switzerland.
  • Guipponi M Geneva University Hospitals-HUG, Service of Genetic Medicine, 4 Rue Gabrielle-Perret-Gentil, Geneva 1211, Switzerland.
  • Murray A 1] The Blizard Institute, Barts and The London School of Medicine, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK [2] LonDownS Consortium, The Wellcome Trust, London NW1 2BE, UK.
  • Groet J 1] The Blizard Institute, Barts and The London School of Medicine, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK [2] LonDownS Consortium, The Wellcome Trust, London NW1 2BE, UK.
  • Giarin E Dipartimento di Salute della Donna e del Bambino, University of Padua, IRP-Istituto di Ricerca Pediatrica-Fondazione Città della Speranza, Via N. Giustiniani 3, 35129 Padua, Italy.
  • Basso G Dipartimento di Salute della Donna e del Bambino, University of Padua, IRP-Istituto di Ricerca Pediatrica-Fondazione Città della Speranza, Via N. Giustiniani 3, 35129 Padua, Italy.
  • Nizetic D 1] The Blizard Institute, Barts and The London School of Medicine, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK [2] LonDownS Consortium, The Wellcome Trust, London NW1 2BE, UK [3] Lee Kong Chian School of Medicine, Nanyang Technological University, Unit 04-11, Proteos Building, 61 Biopolis Drive, Singapore 138673, Singapore [4].
  • Antonarakis SE 1] Department of Genetic Medicine and Development, University of Geneva Medical School, 1 rue Michel Servet, Geneva 1211, Switzerland [2] IGE3 institute of Genetics and Genomics of Geneva, 1 rue Michel Servet, Geneva 1211, Switzerland [3].
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  • 2014-08-09
Published in:
  • Nature communications. - 2014
Child
Chromatin
DNA Mutational Analysis
Down Syndrome
Female
Gene Deletion
Gene Expression Regulation, Leukemic
Humans
Janus Kinase 2
Lymphocytes
Male
Mutation
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Receptors, Cytokine
ras Proteins
English 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.
Language
  • English
Open access status
bronze
Identifiers
Persistent URL
https://sonar.ch/global/documents/232967
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