Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes

Nat Genet. 2017 Mar;49(3):451-456. doi: 10.1038/ng.3772. Epub 2017 Jan 23.

Abstract

Acute megakaryoblastic leukemia (AMKL) is a subtype of acute myeloid leukemia (AML) in which cells morphologically resemble abnormal megakaryoblasts. While rare in adults, AMKL accounts for 4-15% of newly diagnosed childhood AML cases. AMKL in individuals without Down syndrome (non-DS-AMKL) is frequently associated with poor clinical outcomes. Previous efforts have identified chimeric oncogenes in a substantial number of non-DS-AMKL cases, including RBM15-MKL1, CBFA2T3-GLIS2, KMT2A gene rearrangements, and NUP98-KDM5A. However, the etiology of 30-40% of cases remains unknown. To better understand the genomic landscape of non-DS-AMKL, we performed RNA and exome sequencing on specimens from 99 patients (75 pediatric and 24 adult). We demonstrate that pediatric non-DS-AMKL is a heterogeneous malignancy that can be divided into seven subgroups with varying outcomes. These subgroups are characterized by chimeric oncogenes with cooperating mutations in epigenetic and kinase signaling genes. Overall, these data shed light on the etiology of AMKL and provide useful information for the tailoring of treatment.

MeSH terms

  • Animals
  • Down Syndrome / genetics*
  • Exome / genetics
  • Female
  • Gene Rearrangement / genetics
  • Genomics / methods
  • Humans
  • Leukemia, Megakaryoblastic, Acute / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Polymorphism, Single Nucleotide / genetics
  • RNA / genetics
  • Repressor Proteins / genetics
  • Retinoblastoma-Binding Protein 2 / genetics
  • Tumor Suppressor Proteins / genetics

Substances

  • CBFA2T3 protein, human
  • Repressor Proteins
  • Tumor Suppressor Proteins
  • RNA
  • KDM5A protein, human
  • Retinoblastoma-Binding Protein 2