Research Papers:

Genomic complexity and dynamics of clonal evolution in childhood acute myeloid leukemia studied with whole-exome sequencing

Riccardo Masetti _, Ilaria Castelli, Annalisa Astolfi, Salvatore Nicola Bertuccio, Valentina Indio, Marco Togni, Tamara Belotti, Salvatore Serravalle, Giuseppe Tarantino, Marco Zecca, Martina Pigazzi, Giuseppe Basso, Andrea Pession and Franco Locatelli

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Oncotarget. 2016; 7:56746-56757. https://doi.org/10.18632/oncotarget.10778

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Riccardo Masetti1,*, Ilaria Castelli1,*, Annalisa Astolfi2, Salvatore Nicola Bertuccio1, Valentina Indio2, Marco Togni1,3, Tamara Belotti1, Salvatore Serravalle1, Giuseppe Tarantino2, Marco Zecca4, Martina Pigazzi5, Giuseppe Basso5, Andrea Pession1,#, Franco Locatelli6,7,#

1Department of Pediatrics “Lalla Seràgnoli”, Hematology-Oncology Unit, University of Bologna, Bologna, Italy

2Interdepartmental Centre of Cancer Research “G. Prodi”, University of Bologna, Bologna, Italy

3Current address: Stem Cell Group, University College London Cancer Institute, University College London, London, United Kingdom

4Department of Pediatric Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

5Department of Woman and Child Health, Laboratory of Hematology-Oncology, University of Padova, Padova, Italy

6Department of Pediatric Hematology-Oncology, IRCCS Ospedale Bambino Gesù, Rome, Italy

7University of Pavia, Pavia, Italy

*These authors have contributed equally to this work

#Both authors have shared co-senior authorship

Correspondence to:

Riccardo Masetti, email: [email protected]

Keywords: pediatric acute myeloid leukemia, acute myeloid leukemia relapse, whole-exome massively parallel sequencing, SETD2 mutation, FLT3-TKD mutation

Received: April 19, 2016     Accepted: July 10, 2016     Published: July 22, 2016


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.

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