Transcriptome Analysis Offers a Comprehensive Illustration of the Genetic Background of Pediatric Acute Myeloid Leukemia: Japan Pediatric Leukemia/Lymphoma Study Group AML-05

Background Recent advances in the genetic understanding of acute myeloid leukemia (AML) have improved clinical outcomes in pediatric patients. However, approximately 40% of patients with pediatric AML relapse, contributing to a relatively low overall survival (OS) rate of approximately 70%. The objective of this study was to reveal the comprehensive genetic background of pediatric AML. Methods We performed transcriptome analysis (RNA-seq) in 139 of the 369 patients with de novo pediatric AML who were enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 trial and investigated correlations between genetic aberrations and clinical information. Findings Using RNA-seq, we identified 54 in-frame gene fusions and one RUNX1 out-of-frame fusion in 53 out of 139 patients. Moreover, we found at least 258 gene fusions in 369 patients (70%) through RT-PCR and RNA-seq. Six gene rearrangements were newly identified, namely, NPM1-CCDC28A, TRIP12-NPM1, NPM1-DNAJC1, TBL1XR1-RARB, ETV6-CTNNB1, and RUNX1-FNBP1. In addition, we found rare gene rearrangements, namely, MYB-GATA1, NPM1-MLF1, ETV6-NCOA2, ETV6-MECOM, RUNX1-PRDM16, RUNX1-CBFA2T2, and RUNX1-CBFA2T3. Among the remaining 111 patients, KMT2A-PTD, biallelic CEBPA, and NPM1 gene mutations were found in 11, 23, and 17 patients, respectively. These mutations were completely mutually exclusive with any gene fusions. Interpretation RNA-seq unmasked the complexity of gene rearrangements and mutations in pediatric AML. We identified potentially driver alterations in nearly all patients with AML, including novel gene fusions. Based on the results of the RNA-seq, risk stratification should be reconsidered. Funding Statement: Ministry of Education, Culture, Sports, Science, and Technology of Japan and Japan Agency for Medical Research and Development. Declaration of Interests: I have no financial relationships to disclose. Ethics Approval Statement: The present study was conducted in accordance with the Declaration of Helsinki and approved by the institutional review boards of Gunma Children’s Medical Center and the participating institutes and the ethical review board of the JPLSG AML-05 trial.