Recurrent CCND3 Mutations in MLL-rearranged Acute Myeloid Leukemia

Blood Adv. 2018 Nov 13;2(21):2879-2889. doi: 10.1182/bloodadvances.2018019398.

Abstract

In acute myeloid leukemia (AML), MLL (KMT2A) rearrangements are among the most frequent chromosomal abnormalities; however, knowledge of the genetic landscape of MLL-rearranged AML is limited. In this study, we performed whole-exome sequencing (n = 9) and targeted sequencing (n = 56) of samples from pediatric MLL-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 MLL-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 MLL-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 CCND3 mutations were identified in 5 pediatric MLL-rearranged AML patients (8.9%) and 2 adult MLL-rearranged AML patients (3.3%). Recurrent mutations of CCND1 (n = 3, 2.9%) and CCND2 (n = 8, 7.6%) were found in pediatric t(8;21) AML patients, whereas no CCND3 mutations were found, suggesting that D-type cyclins exhibit a subtype-specific mutation pattern in AML. Treatment of MLL-rearranged AML cell lines with CDK4/6 inhibitors (abemaciclib and palbociclib) blocked G1 to S phase cell-cycle progression and impaired proliferation. Pediatric MLL-MLLT3-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) (P = .048 and .046, respectively). These data provide insights into the genetics of MLL-rearranged AML and suggest therapeutic strategies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Child
  • Child, Preschool
  • Cyclin D / genetics
  • Cyclin D3 / antagonists & inhibitors
  • Cyclin D3 / genetics*
  • Cyclin D3 / metabolism
  • DNA Copy Number Variations
  • Female
  • G1 Phase Cell Cycle Checkpoints / drug effects
  • Gene Rearrangement
  • Histone-Lysine N-Methyltransferase / genetics*
  • Humans
  • Infant
  • Infant, Newborn
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / mortality
  • Leukemia, Myeloid, Acute / pathology*
  • Male
  • Mutation
  • Myeloid-Lymphoid Leukemia Protein / genetics*
  • Protein Kinase Inhibitors / pharmacology
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Recurrence
  • Survival Rate

Substances

  • CCND3 protein, human
  • Cyclin D
  • Cyclin D3
  • KMT2A protein, human
  • Protein Kinase Inhibitors
  • RNA, Small Interfering
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase