Abstract
To induce and sustain the leukaemogenic process, MLL-AF4+ leukaemia seems to require very few genetic alterations in addition to the fusion gene itself. Studies of infant and paediatric patients with MLL-AF4+ B cell precursor acute lymphoblastic leukaemia (BCP-ALL) have reported mutations in KRAS and NRAS with incidences ranging from 25 to 50%. Whereas previous studies employed Sanger sequencing, here we used next generation amplicon deep sequencing for in depth evaluation of RAS mutations in 36 paediatric patients at diagnosis of MLL-AF4+ leukaemia. RAS mutations including those in small sub-clones were detected in 63.9% of patients. Furthermore, the mutational analysis of 17 paired samples at diagnosis and relapse revealed complex RAS clone dynamics and showed that the mutated clones present at relapse were almost all originated from clones that were already detectable at diagnosis and survived to the initial therapy. Finally, we showed that mutated patients were indeed characterized by a RAS related signature at both transcriptional and protein levels and that the targeting of the RAS pathway could be of beneficial for treatment of MLL-AF4+ BCP-ALL clones carrying somatic RAS mutations.
Highlights
To induce and sustain the leukaemogenic process, MLL-AF4+ leukaemia seems to require very few genetic alterations in addition to the fusion gene itself
A transgenic mouse model simultaneously expressing MLL-AF4 and an activated KRAS mutated gene showed a shortened leukaemia latency[11], which prompted for renewed KRAS and NRAS mutation screenings in MLL rearranged and wild type infant and paediatric patients
Several works showed that B cell precursor (BCP) MLL-AF4 rearranged leukaemia is characterized by a very low rate of genetic alteration[13,14,15] and using Sanger sequencing a significant amount of data on the mutational status of RAS genes in infants and paediatric patients with MLL-AF4 leukaemia were previously obtained[23,35,36,37]
Summary
To induce and sustain the leukaemogenic process, MLL-AF4+ leukaemia seems to require very few genetic alterations in addition to the fusion gene itself. Whereas previous studies employed Sanger sequencing, here we used generation amplicon deep sequencing for in depth evaluation of RAS mutations in 36 paediatric patients at diagnosis of MLL-AF4+ leukaemia. Several studies investigated the leukaemogenic properties of both fusion genes in vitro and in vivo providing important insights into the pathogenesis of MLL-related leukaemia[3,5,6]. A transgenic mouse model simultaneously expressing MLL-AF4 and an activated KRAS mutated gene showed a shortened leukaemia latency[11], which prompted for renewed KRAS and NRAS mutation screenings in MLL rearranged and wild type infant and paediatric patients. We deeply investigated the RAS mutational status in infant and paediatric MLL-AF4+patients and reported the results of ultra sensitive deep mutation sequencing of Department of Woman and Child Health, University of Padua, Via Giustiniani 3, 35128 Padua, Italy.
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