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

Riccardo Masetti, Ilaria Castelli, A. Astolfi, Salvatore Nicola Bertuccio, Valentina Indio, Marco Togni, Tamara Belotti, S. Serravalle, Giuseppe Tarantino, Marco Zecca, M. Pigazzi, Giuseppe Basso, Andrea Pession, Franco Locatelli

Research output: Contribution to journalArticle

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%). BiCEBPa 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.

Original languageEnglish
Pages (from-to)56746-56757
Number of pages12
JournalOncotarget
Volume7
Issue number35
DOIs
Publication statusPublished - 2016

Keywords

  • Acute myeloid leukemia relapse
  • FLT3-TKD mutation
  • Pediatric acute myeloid leukemia
  • SETD2 mutation
  • Whole-exome massively parallel sequencing

ASJC Scopus subject areas

  • Oncology

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    Masetti, R., Castelli, I., Astolfi, A., Bertuccio, S. N., Indio, V., Togni, M., Belotti, T., Serravalle, S., Tarantino, G., Zecca, M., Pigazzi, M., Basso, G., Pession, A., & Locatelli, F. (2016). Genomic complexity and dynamics of clonal evolution in childhood acute myeloid leukemia studied with whole-exome sequencing. Oncotarget, 7(35), 56746-56757. https://doi.org/10.18632/oncotarget.10778