Mutations of cMYC Exon 2 Are a Rare but Recurrent Abnormality in Adult Patients with Acute Myeloid Leukemia (AML)

Next generation sequencing (NGS) has been extensively used to characterize the molecular background in patients with AML. Several novel recurrent alterations have been discovered, such as the common mutations in the IDH-genes and in DNMT3A. We aimed to use this technology to characterize patients failing induction chemotherapy. To better understand mechanisms of resistance, we applied whole exome based NGS screening in younger AML patients failing conventional induction chemotherapy. In a group of 29 patients, two patients showed mutations in cMYC exon 2. Similar mutations have been reported in diffuse large B-cell lymphoma (DLBCL), Burkitt 's lymphoma and aggressive HIV associated lymphomas. These alterations cluster in the aminoterminal part of the protein and lead to stabilization of the MYC protein, MYC activation and evasion of TP53 mediated tumor surveillance. MYC mutations have only occasionally been described in AML before, but amplification of cMYC or activation of this important oncoprotein via other cellular pathways has been linked to aggressive disease and resistance to treatment. So, in order to better understand the prevalence and the prognostic implications of cMYC mutations in adult AML, we screened a set of more than 1200 patients with AML and advanced MDS for the presence of mutations in the cMYC- gene. Patients and Methods: We retrospectively characterized genomic DNA samples taken at the time of first diagnosis from 1281 patients with AML treated in the AML96 protocol of the Study Alliance Leukemia (SAL). Since all reported mutations cluster in cMYC exon 2, this region was analyzed using conventional Sanger sequencing. In cMYC-mutated patients, a set of 54 genes (Trusight Myeloid Panel) covering commonly mutated genes in myeloid disease was analyzed for alterations using next generation sequencing (NGS) on a MiSEQ instrument. Results: An exon 2 mutation in cMYC was found in 14/1281 (1.1%) of the patients, all mutations clustered in the the MbI-domain between codons 57 and 62, with codon P59 being the most frequently mutated position. Analysis of the allelic burden indicated that the mutations occurred early in the disease. Correlation with clinical, cytogenetic and molecular data showed, that the mutations were predominantly found in patients with normal or intermediate risk karyotype, but they were also seen in good risk and high risk patients. Strikingly, 9 of 14 patients (77%) showed an NPM1-mutation (p=.004) and 7 of 14 (50%) were FLT3-ITD mutated (p=.02). The extended NGS-characterization did not reveal any additional specific secondary alterations associated with this mutation. MYC mutations were found in all FAB-subtypes excluding FAB M0, no significant differences were seen for other clinical variables, including age, sex, white blood cell and bone marrow blast counts. In univariate as well as multivariate analysis, patients with cMYC mutations did not show any significant difference in the rate of complete remission (CR), the event free and the overall survival, even when restricted to subgroups such as patients with normal karyotype or with NPM1 mutations. Conclusions: This study showed that mutations in cMYC exon 2 are a rare but recurrent abnormality in AML. The mutations are significantly enriched in patients with mutant NPM1 and FLT3-ITD, but based on our analysis, they seem not to have any prognostic implications.