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

Developmental cell | 2018

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-7Rprogenitor 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-7Rcompartment, 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.

Pubmed ID: 29290585 RIS Download

Mesh terms: 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

Associated grants

  • Agency: Medical Research Council, United Kingdom
    Id: MC_UU_12009/10
  • Agency: Wellcome Trust, United Kingdom
    Id: (100056/Z/12/Z
  • Agency: Medical Research Council, United Kingdom
    Id: MC_PC_15004
  • Agency: Medical Research Council, United Kingdom
    Id: MR/K017047/1
  • Agency: Medical Research Council, United Kingdom
    Id: G0700089
  • Agency: Medical Research Council, United Kingdom
    Id: G0801073
  • Agency: Medical Research Council, United Kingdom
    Id: MC_UU_12009/5
  • Agency: Wellcome Trust, United Kingdom
  • Agency: Medical Research Council, United Kingdom
    Id: G0501838

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