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

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

来源：Developmental Cell, 2018, 44(3): 362-+.

DOI：10.1016/j.devcel.2017.12.005

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.

• 出版日期2018-2-5