Genetically distinct leukemic stem cells in human CD34- acute myeloid leukemia are arrested at a hemopoietic precursor-like stage

Lynn Quek, Georg W Otto, Catherine Garnett, Ludovic Lhermitte, Dimitris Karamitros, Bilyana Stoilova, I-Jun Lau, Jessica Doondeea, Batchimeg Usukhbayar, Alison Kennedy, Marlen Metzner, Nicolas Goardon, Adam Ivey, Christopher Allen, Rosemary Gale, Benjamin Davies, Alexander Sternberg, Sally Killick, Hannah Hunter, Paul CahalinAndrew Price, Andrew Carr, Mike Griffiths, Paul Virgo, Stephen Mackinnon, David Grimwade, Sylvie Freeman, Nigel Russell, Charles Craddock, Adam Mead, Andrew Peniket, Catherine Porcher, Paresh Vyas

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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 ∼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.

Original languageEnglish
Pages (from-to)1513-35
Number of pages23
JournalThe Journal of Experimental Medicine
Issue number8
Early online date4 Jul 2016
Publication statusPublished - 25 Jul 2016


  • Journal Article


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