期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 213, 期 8, 页码 1513-1535出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20151775
关键词
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资金
- Medical Research Council (MRC) Disease Team Award
- MRC Disease Team Award [G1000729]
- MRC Molecular Haematology Unit [MC_UU_12009/11]
- Oxford Partnership Comprehensive Biomedical Research Centre (National Institute for Health Research [NIHR] BRC funding scheme)
- Cancer Research UK [C7893/A12796]
- Oxford NIHR Musculoskeletal Biomedical Research Unit
- NIHR [RP-PG-0108-10093]
- MRC [MC_UU_12009/11, MC_UU_12009/16, MR/L006340/1, MR/M00919X/1, G1000729, MC_UU_12009/9] Funding Source: UKRI
- Medical Research Council [MC_UU_12009/11, MR/M00919X/1, MC_UU_12009/9, MC_UU_12009/16, G1000729, MR/L006340/1, G1000801c] Funding Source: researchfish
- National Institute for Health Research [RP-PG-0108-10093] Funding Source: researchfish
Our understanding of the perturbation of normal cellular differentiation hierarchies to create tumor-propagating stem cell populations is incomplete. In human acute myeloid leukemia (AML), current models suggest transformation creates leukemic stem cell (LSC) populations arrested at a progenitor-like stage expressing cell surface CD34. We show that in similar to 25% of AML, with a distinct genetic mutation pattern where >98% of cells are CD34(-), there are multiple, nonhierarchically arranged CD34(+) and CD34(-) LSC populations. Within CD34(-) and CD34(+) LSC-containing populations, LSC frequencies are similar; there are shared clonal structures and near-identical transcriptional signatures. CD34(-) LSCs have disordered global transcription profiles, but these profiles are enriched for transcriptional signatures of normal CD34(-) mature granulocyte-macrophage precursors, downstream of progenitors. But unlike mature precursors, LSCs express multiple normal stem cell transcriptional regulators previously implicated in LSC function. This suggests a new refined model of the relationship between LSCs and normal hemopoiesis in which the nature of genetic/epigenetic changes determines the disordered transcriptional program, resulting in LSC differentiation arrest at stages that are most like either progenitor or precursor stages of hemopoiesis.
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