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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskriftPeer review

33 !!Citations (SciVal)

Sammanfattning

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 CD19IL-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 CD19IL-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. Böiers, Richardson et al. explore the potential for a developmental susceptibility to childhood acute lymphoblastic leukemia. Characterization of earliest B cell progenitors in human fetal liver identified a unique progenitor compartment that can be recapitulated using human pluripotent stem cells to model the impact of the pre-leukemia-initiating oncogene ETV6-RUNX1.

Originalspråkengelska
Sidor (från-till)362-377.e7
TidskriftDevelopmental Cell
Volym44
Utgåva3
DOI
StatusPublished - 2018 feb 5

Ämnesklassifikation (UKÄ)

  • Cancer och onkologi
  • Cell- och molekylärbiologi

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