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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
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2014
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| Online Access: | https://hdl.handle.net/10356/101511 http://hdl.handle.net/10220/24153 |
| _version_ | 1826119739887321088 |
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| author | 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. |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) 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. |
| author_sort | Nikolaev, Sergey I. |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T05:05:02Z |
| format | Journal Article |
| id | ntu-10356/101511 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T05:05:02Z |
| publishDate | 2014 |
| record_format | dspace |
| spelling | ntu-10356/1015112022-02-16T16:29:27Z Frequent cases of RAS-mutated down syndrome acute lymphoblastic leukaemia lack JAK2 mutations 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. Lee Kong Chian School of Medicine (LKCMedicine) DRNTU::Science::Biological sciences::Human anatomy and physiology 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 version 2014-10-30T01:57:03Z 2019-12-06T20:39:33Z 2014-10-30T01:57:03Z 2019-12-06T20:39:33Z 2014 2014 Journal Article 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. 2041-1723 https://hdl.handle.net/10356/101511 http://hdl.handle.net/10220/24153 10.1038/ncomms5654 25105841 en Nature communications © 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]. 23 p. application/pdf |
| spellingShingle | DRNTU::Science::Biological sciences::Human anatomy and physiology 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. Frequent cases of RAS-mutated down syndrome acute lymphoblastic leukaemia lack JAK2 mutations |
| title | Frequent cases of RAS-mutated down syndrome acute lymphoblastic leukaemia lack JAK2 mutations |
| title_full | Frequent cases of RAS-mutated down syndrome acute lymphoblastic leukaemia lack JAK2 mutations |
| title_fullStr | Frequent cases of RAS-mutated down syndrome acute lymphoblastic leukaemia lack JAK2 mutations |
| title_full_unstemmed | Frequent cases of RAS-mutated down syndrome acute lymphoblastic leukaemia lack JAK2 mutations |
| title_short | Frequent cases of RAS-mutated down syndrome acute lymphoblastic leukaemia lack JAK2 mutations |
| title_sort | frequent cases of ras mutated down syndrome acute lymphoblastic leukaemia lack jak2 mutations |
| topic | DRNTU::Science::Biological sciences::Human anatomy and physiology |
| url | https://hdl.handle.net/10356/101511 http://hdl.handle.net/10220/24153 |
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