Title | A Human IPS Model Implicates Embryonic B-Myeloid Fate Restriction as Developmental Susceptibility to B Acute Lymphoblastic Leukemia-Associated ETV6-RUNX1. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Böiers C, Richardson SE, Laycock E, Zriwil A, Turati VA, Brown J, Wray JP, Wang D, James C, Herrero J, Sitnicka E, Karlsson S, Smith AG, Jacobsen SErik W, Enver T |
Journal | Dev Cell |
Volume | 44 |
Issue | 3 |
Pagination | 362-377.e7 |
Date Published | 2018 02 05 |
ISSN | 1878-1551 |
Keywords | 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 |
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 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. |
DOI | 10.1016/j.devcel.2017.12.005 |
Alternate Journal | Dev. Cell |
PubMed ID | 29290585 |
PubMed Central ID | PMC5807056 |
Grant List | MC_UU_12009/10 / / Medical Research Council / United Kingdom (100056/Z/12/Z / / Wellcome Trust / United Kingdom MC_PC_15004 / / Medical Research Council / United Kingdom G0700089 / / Medical Research Council / United Kingdom G0801073 / / Medical Research Council / United Kingdom MC_UU_12009/5 / / Medical Research Council / United Kingdom / / Wellcome Trust / United Kingdom G0501838 / / Medical Research Council / United Kingdom |