Genetically distinct leukemic stem cells in human CD34− acute myeloid leukemia are arrested at a hemopoietic precursor-like stage
L Quek, GW Otto, C Garnett, L Lhermitte… - Journal of Experimental …, 2016 - rupress.org
L Quek, GW Otto, C Garnett, L Lhermitte, D Karamitros, B Stoilova, IJ Lau, J Doondeea…
Journal of Experimental Medicine, 2016•rupress.orgOur 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 …
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 …
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.
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