TY - JOUR
T1 - Frequent cases of RAS-mutated Down syndrome acute lymphoblastic leukaemia lack JAK2 mutations
AU - Nikolaev, Sergey I.
AU - Garieri, Marco
AU - Santoni, Federico
AU - Falconnet, Emilie
AU - Ribaux, Pascale
AU - Guipponi, Michel
AU - Murray, Aoife
AU - Groet, Jürgen
AU - Giarin, Emanuela
AU - Basso, Giuseppe
AU - Nizetic, Dean
AU - Antonarakis, Stylianos E.
N1 - Funding Information:
This work was supported by KKL632 grant from the Kay Kendall Leukaemia Fund, Jerome Lejeune Foundation project grant 2011B-960, the Wellcome Trust Strategic Award WT 098330/Z/12/Z (The LonDownS Consortium) and the Lee Kong Chian School of Medicine, Nanyang Technological University-Singapore start-up funding grant M4230024 to D.N.; Swiss Cancer League (LSCC 2939-02-2012) and Dinu Lipatti 2014 grants to S.I.N.; SNF 144082, ERC 249968 and Foundation ‘ChildCare’ grants to S.E.A.; and by Cariparo bando ricerca pediatrica and by European commission (FP7 ENCCA, 261474, Trancan PER-2011-2353841) to G.B.
PY - 2014/8/8
Y1 - 2014/8/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84907341405&partnerID=8YFLogxK
U2 - 10.1038/ncomms5654
DO - 10.1038/ncomms5654
M3 - Article
C2 - 25105841
AN - SCOPUS:84907341405
SN - 2041-1723
VL - 5
JO - Nature Communications
JF - Nature Communications
M1 - 4654
ER -