A Human IPS Model Implicates Embryonic B-Myeloid Fate Restriction as Developmental Susceptibility to B Acute Lymphoblastic Leukemia-Associated ETV6-RUNX1

Charlotta Böiers, Simon E Richardson, Emma Laycock, Alya Zriwil, Virginia A Turati, John Brown, Jason P Wray, Dapeng Wang, Chela James, Javier Herrero, Ewa Sitnicka, Stefan Karlsson, Andrew J H Smith, Sten Erik W Jacobsen, Tariq Enver

Research output: Contribution to journalArticlepeer-review

Abstract

ETV6-RUNX1 is associated with childhood acute B-lymphoblastic leukemia (cALL) functioning as a first-hit mutation that initiates a clinically silent pre-leukemia in utero. Because lineage commitment hierarchies differ between embryo and adult, and the impact of oncogenes is cell-context dependent, we hypothesized that the childhood affiliation of ETV6-RUNX1 cALL reflects its origins in a progenitor unique to embryonic life. We characterize the first emerging B cells in first-trimester human embryos, identifying a developmentally restricted CD19-IL-7R+ progenitor compartment, which transitions from a myeloid to lymphoid program during ontogeny. This developmental series is recapitulated in differentiating human pluripotent stem cells (hPSCs), thereby providing a model for the initiation of cALL. Genome-engineered hPSCs expressing ETV6-RUNX1 from the endogenous ETV6 locus show expansion of the CD19-IL-7R+ compartment, show a partial block in B lineage commitment, and produce proB cells with aberrant myeloid gene expression signatures and potential: features (collectively) consistent with a pre-leukemic state.

Original languageEnglish
Pages (from-to)362-377.e7
Number of pages23
JournalDevelopmental Cell
Volume44
Issue number3
Early online date28 Dec 2017
DOIs
Publication statusPublished - 5 Feb 2018

Keywords

  • Acute Disease
  • B-Lymphocytes/metabolism
  • Core Binding Factor Alpha 2 Subunit/genetics
  • Embryonic Development
  • Female
  • Gene Expression Regulation, Leukemic
  • Humans
  • Induced Pluripotent Stem Cells/metabolism
  • Models, Biological
  • Myeloid Cells/metabolism
  • Oncogene Proteins, Fusion/genetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism
  • Pregnancy
  • Pregnancy Trimester, First
  • Receptors, Interleukin-7
  • Transcriptome

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