The landscape of somatic mutations in Down syndrome-related myeloid disorders

Nat Genet. 2013 Nov;45(11):1293-9. doi: 10.1038/ng.2759. Epub 2013 Sep 22.


Transient abnormal myelopoiesis (TAM) is a myeloid proliferation resembling acute megakaryoblastic leukemia (AMKL), mostly affecting perinatal infants with Down syndrome. Although self-limiting in a majority of cases, TAM may evolve as non-self-limiting AMKL after spontaneous remission (DS-AMKL). Pathogenesis of these Down syndrome-related myeloid disorders is poorly understood, except for GATA1 mutations found in most cases. Here we report genomic profiling of 41 TAM, 49 DS-AMKL and 19 non-DS-AMKL samples, including whole-genome and/or whole-exome sequencing of 15 TAM and 14 DS-AMKL samples. TAM appears to be caused by a single GATA1 mutation and constitutive trisomy 21. Subsequent AMKL evolves from a pre-existing TAM clone through the acquisition of additional mutations, with major mutational targets including multiple cohesin components (53%), CTCF (20%), and EZH2, KANSL1 and other epigenetic regulators (45%), as well as common signaling pathways, such as the JAK family kinases, MPL, SH2B3 (LNK) and multiple RAS pathway genes (47%).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • CCCTC-Binding Factor
  • Cell Cycle Proteins / genetics
  • Cell Proliferation
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomes, Human, Pair 21 / genetics
  • Down Syndrome / genetics*
  • Down Syndrome / immunology*
  • Enhancer of Zeste Homolog 2 Protein
  • GATA1 Transcription Factor / genetics
  • Gene Expression Profiling
  • Humans
  • Leukemia, Megakaryoblastic, Acute / genetics*
  • Leukemoid Reaction / genetics*
  • Myeloid Cells
  • Myeloproliferative Disorders / genetics
  • Nuclear Proteins / genetics
  • Polycomb Repressive Complex 2 / genetics
  • Repressor Proteins / genetics
  • Sequence Analysis, DNA


  • CCCTC-Binding Factor
  • CTCF protein, human
  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • GATA1 Transcription Factor
  • GATA1 protein, human
  • NSL1 protein, human
  • Nuclear Proteins
  • Repressor Proteins
  • cohesins
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Polycomb Repressive Complex 2

Supplementary concepts

  • Myeloproliferative Syndrome, Transient