Recurrent CCND3 mutations in MLL-rearranged acute myeloid leukemia

Abstract

In acute myeloid leukemia (AML), <i>MLL</i> (<i>KMT2A</i>) rearrangements are among the most frequent chromosomal abnormalities; however, knowledge of the genetic landscape of <i>MLL</i>-rearranged AML is limited. In this study, we performed whole-exome sequencing (n = 9) and targeted sequencing (n = 56) of samples from pediatric <i>MLL</i>-rearranged AML patients enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 study. Additionally, we analyzed 105 pediatric t(8;21) AML samples and 30 adult <i>MLL</i>-rearranged AML samples. RNA-sequencing data from 31 patients published in a previous study were also reanalyzed. As a result, we identified 115 mutations in pediatric <i>MLL</i>-rearranged AML patients (2.1 mutations/patient), with mutations in signaling pathway genes being the most frequently detected (60.7%). Mutations in genes associated with epigenetic regulation (21.4%), transcription factors (16.1%), and the cohesin complex (8.9%) were also commonly detected. Novel <i>CCND3</i> mutations were identified in 5 pediatric <i>MLL</i>-rearranged AML patients (8.9%) and 2 adult <i>MLL</i>-rearranged AML patients (3.3%). Recurrent mutations of <i>CCND1</i> (n = 3, 2.9%) and <i>CCND2</i> (n = 8, 7.6%) were found in pediatric t(8;21) AML patients, whereas no <i>CCND3</i> mutations were found, suggesting that D-type cyclins exhibit a subtype-specific mutation pattern in AML. Treatment of <i>MLL</i>-rearranged AML cell lines with CDK4/6 inhibitors (abemaciclib and palbociclib) blocked G1 to S phase cell-cycle progression and impaired proliferation. Pediatric <i>MLL-MLLT3</i>-rearranged AML patients with coexisting mutations (n = 16) had significantly reduced relapse-free survival and overall survival compared with those without coexisting mutations (n = 9) (<i>P</i> = .048 and .046, respectively). These data provide insights into the genetics of <i>MLL</i>-rearranged AML and suggest therapeutic strategies.