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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 publication




Journal article


Dev Cell

Publication Date





362 - 377.e7


B cell, CRISPR/Cas9, ETV6-RUNX1, acute lymphoblastic leukemia, genome engineering, human fetal lymphopoiesis, human pluripotent stem cells, in vitro B cell differentiation, Acute Disease, B-Lymphocytes, Core Binding Factor Alpha 2 Subunit, Embryonic Development, Female, Gene Expression Regulation, Leukemic, Humans, Induced Pluripotent Stem Cells, Models, Biological, Myeloid Cells, Oncogene Proteins, Fusion, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Pregnancy, Pregnancy Trimester, First, Receptors, Interleukin-7, Transcriptome