Acquisition or Loss of Gene Mutations Occurs in Relapsed Pediatric Acute Myeloid Leukemia: A Comparative Analysis of Paired Matched Diagnosis and Relapse Bone Marrow Samples

Relapse is the major cause of treatment failure in patients with acute myeloid leukemia (AML). The molecular pathogenesis in the relapse of AML is not well understood. A better understanding of molecular aberrations of relapsed AML will further improve the treatment outcome. In the present study, we aimed to determine the role of gene mutations in the relapse of de novo pediatric AML by comparative analysis of the paired matched diagnosis and relapse samples for the mutational status of 18 known mutated genes involved in myeloid neoplasms.

Two hundred and six children aged below 18 with de novo AML were diagnosed at Chang Gung Children's Hospital, Taoyuan, Taiwan and MacKay Memorial Hospital, Taipei, Taiwan, between 1996 and 2011. They were treated with Taiwan Pediatric Oncology Group AML-97 Protocol (Leukemia 2006). Sixty patients had relapses of leukemia, 46 of them had paired diagnosis and relapse bone marrow samples available for examination on the 18 mutated genes, including FLT3-ITD, FLT3-TKD, C-KIT, C-FMS, NRAS, KRAS, PTPN11, JAK2V617F, RUNX1, CEBPα, NPM1, MLL-PTD, WT1, P53, DNMT3A, IDH1, IDH2 and ASXL1. Mutational analysis was performed with PCR-based assay followed by direct sequencing.

The results are summarized in Table 1. Fifteen patients with one mutated gene and 4 with two mutated genes at diagnosis remained unchanged at relapse, all the mutations detected were not present in the complete remission samples. Twenty-five patients without gene mutations at diagnosis did not acquire mutations at relapse. Six patients acquired gene mutations, 5 WT1 and one P53 mutations, indicating clonal evolution during leukemia relapse. Another 7 patients lost gene mutations including 2 FLT3-ITD, 2 FLT3-TKD, one NRAS, one JAK2V617F and one IDH1genes; notably, 4 of them harboring other mutated genes at relapse, suggesting outgrowth or clonal selection of these mutated clone(s) in relapse.

Our study showed that gene mutation status in the majority of pediatric AML patients remained unchanged at both diagnosis and relapse, but acquisition or loss of gene mutations may occur at relapse.

No relevant conflicts of interest to declare.