The final published article can be found here: http://dx.doi.org/10.1038/ncomms5654This 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

Antonarakis, SE

Basso, G

Falconnet, E

Garieri, M

Giarin, E

Groet, J

Guipponi, M

Murray, A

Nikolaev, SI

Nizetic, D

Ribaux, P

Santoni, F

Nature Communications

PubMed

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.Accepted versio

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.

Digital Repository - Nanyang Technological University

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

Sergey I. Nikolaev

Marco Garieri

Federico Santoni

Emilie Falconnet

Pascale Ribaux

Michel Guipponi

Aoife Murray

Jürgen Groet

Emanuela Giarin

Giuseppe Basso

Dean Nizetic

Stylianos E. Antonarakis

Crossref

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

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

Nikolaev, Sergey Igorievich

Ribaux, Pascale Garlonne

Antonarakis, Stylianos

Archive ouverte UNIGE

Nikolaev, S. I.

Garieri, M.

Santoni, F.

Falconnet, E.

Ribaux, P.

Guipponi, M.

Murray, A.

Groet, J.

Giarin, E.

Basso, G.

Nizetic, D.

Antonarakis, S. E.

Serveur académique lausannois

Queen Mary Research Online

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

Jürgen Groet

BASSO, GIUSEPPE

Archivio istituzionale della ricerca - Università di Padova

DR-NTU (Digital Repository of NTU)

https://qmro.qmul.ac.uk/xmlui/bitstream/handle/123456789/7642/NIZETICFrequentCases2014.pdf?sequence=2

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

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