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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.

TitleA Human IPS Model Implicates Embryonic B-Myeloid Fate Restriction as Developmental Susceptibility to B Acute Lymphoblastic Leukemia-Associated ETV6-RUNX1.
Publication TypeJournal Article
Year of Publication2018
AuthorsBöiers 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
JournalDev Cell
Volume44
Issue3
Pagination362-377.e7
Date Published2018 02 05
ISSN1878-1551
KeywordsAcute 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.

DOI10.1016/j.devcel.2017.12.005
Alternate JournalDev. Cell
PubMed ID29290585
PubMed Central IDPMC5807056
Grant ListMC_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
Publication institute
CRM