Clinical impact of genomic characterization of 15 patients with acute megakaryoblastic leukemia-related malignancies

Cold Spring Harb Mol Case Stud. 2021 Apr 8;7(2):a005975. doi: 10.1101/mcs.a005975. Print 2021 Apr.


Acute megakaryoblastic leukemia (AMKL) is a rare subtype of acute myeloid leukemia but is approximately 500 times more likely to develop in children with Down syndrome (DS) through transformation of transient abnormal myelopoiesis (TAM). This study investigates the clinical significance of genomic heterogeneity of AMKL in children with and without DS and in children with TAM. Genomic evaluation of nine patients with DS-related TAM or AMKL, and six patients with non-DS AMKL, included conventional cytogenetics and a comprehensive next-generation sequencing panel for single-nucleotide variants/indels and copy-number variants in 118 genes and fusions involving 110 genes. Recurrent gene fusions were found in all patients with non-DS, including two individuals with complex genomes and either a NUP98-KDM5A or a KMT2A-MLLT6 fusion, and the remaining harbored a CBFA2T3-GLIS2 fusion, which arose from both typical and atypical cytogenetic mechanisms. These fusions guided treatment protocols and resulted in a change in diagnosis in two patients. The nine patients with DS had constitutional trisomy 21 and somatic GATA1 mutations, and those with DS-AMKL had two to four additional clinically significant somatic mutations. Comprehensive genomic characterization provides critical information for diagnosis, risk stratification, and treatment decisions for patients with AMKL. Continued genetic and clinical characterization of these rare cancers will aid in improving patient management.

Keywords: acute megakaryocytic leukemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Child
  • Child, Preschool
  • Chromosomes
  • DNA-Binding Proteins / genetics
  • Down Syndrome / complications
  • Down Syndrome / genetics
  • Female
  • GATA1 Transcription Factor
  • Genetic Predisposition to Disease / genetics
  • Genomics*
  • High-Throughput Nucleotide Sequencing
  • Histone-Lysine N-Methyltransferase / genetics
  • Humans
  • Infant
  • Infant, Newborn
  • Karyotype
  • Kruppel-Like Transcription Factors / genetics
  • Leukemia / genetics*
  • Leukemia, Megakaryoblastic, Acute / genetics*
  • Leukemoid Reaction / genetics
  • Male
  • Myeloid-Lymphoid Leukemia Protein / genetics
  • Neoplasm Proteins / genetics
  • Neoplasms / genetics*
  • Repressor Proteins / genetics
  • Retinoblastoma-Binding Protein 2 / genetics


  • CBFA2T3 protein, human
  • DNA-Binding Proteins
  • GATA1 Transcription Factor
  • GATA1 protein, human
  • GLIS2 protein, human
  • KMT2A protein, human
  • Kruppel-Like Transcription Factors
  • MLLT6 protein, human
  • Neoplasm Proteins
  • Repressor Proteins
  • Myeloid-Lymphoid Leukemia Protein
  • KDM5A protein, human
  • Retinoblastoma-Binding Protein 2
  • Histone-Lysine N-Methyltransferase

Supplementary concepts

  • Myeloproliferative Syndrome, Transient