Masetti, R;
Castelli, I;
Astolfi, A;
Bertuccio, SN;
Indio, V;
Togni, M;
Belotti, T;
... Locatelli, F; + view all
(2016)
Genomic complexity and dynamics of clonal evolution in childhood acute myeloid leukemia studied with whole-exome sequencing.
Oncotarget
, 7
(35)
pp. 56746-56757.
10.18632/oncotarget.10778.
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Abstract
Despite significant improvement in treatment of childhood acute myeloid leukemia (AML), 30% of patients experience disease recurrence, which is still the major cause of treatment failure and death in these patients. To investigate molecular mechanisms underlying relapse, we performed whole-exome sequencing of diagnosis-relapse pairs and matched remission samples from 4 pediatric AML patients without recurrent cytogenetic alterations. Candidate driver mutations were selected for targeted deep sequencing at high coverage, suitable to detect small subclones (0.12%). BiCEBPα mutation was found to be stable and highly penetrant, representing a separate biological and clinical entity, unlike WT1 mutations, which were extremely unstable. Among the mutational patterns underlying relapse, we detected the acquisition of proliferative advantage by signaling activation (PTPN11 and FLT3-TKD mutations) and the increased resistance to apoptosis (hyperactivation of TYK2). We also found a previously undescribed feature of AML, consisting of a hypermutator phenotype caused by SETD2 inactivation. The consequent accumulation of new mutations promotes the adaptability of the leukemia, contributing to clonal selection. We report a novel ASXL3 mutation characterizing a very small subclone (<1%) present at diagnosis and undergoing expansion (60%) at relapse. Taken together, these findings provide molecular clues for designing optimal therapeutic strategies, in terms of target selection, adequate schedule design and reliable response-monitoring techniques.
| Type: | Article |
|---|---|
| Title: | Genomic complexity and dynamics of clonal evolution in childhood acute myeloid leukemia studied with whole-exome sequencing |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.18632/oncotarget.10778 |
| Publisher version: | http://dx.doi.org/10.18632/oncotarget.10778 |
| Additional information: | This article is licensed under a Creative Commons Attribution 3.0 License. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Oncology, Cell Biology, pediatric acute myeloid leukemia, acute myeloid leukemia relapse, whole-exome massively parallel sequencing, SETD2 mutation, FLT3-TKD mutation, ACUTE LYMPHOBLASTIC-LEUKEMIA, CHILDRENS ONCOLOGY GROUP, PROGNOSTIC IMPLICATIONS, EPIGENETIC REGULATORS, RESIDUAL DISEASE, RANDOMIZED-TRIAL, CEBPA MUTATIONS, PEDIATRIC AML, COPY NUMBER, RELAPSE |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/1514360 |
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