TY - JOUR
T1 - Genetically distinct leukemic stem cells in human CD34- acute myeloid leukemia are arrested at a hemopoietic precursor-like stage
AU - Quek, Lynn
AU - Otto, Georg W
AU - Garnett, Catherine
AU - Lhermitte, Ludovic
AU - Karamitros, Dimitris
AU - Stoilova, Bilyana
AU - Lau, I-Jun
AU - Doondeea, Jessica
AU - Usukhbayar, Batchimeg
AU - Kennedy, Alison
AU - Metzner, Marlen
AU - Goardon, Nicolas
AU - Ivey, Adam
AU - Allen, Christopher
AU - Gale, Rosemary
AU - Davies, Benjamin
AU - Sternberg, Alexander
AU - Killick, Sally
AU - Hunter, Hannah
AU - Cahalin, Paul
AU - Price, Andrew
AU - Carr, Andrew
AU - Griffiths, Mike
AU - Virgo, Paul
AU - Mackinnon, Stephen
AU - Grimwade, David
AU - Freeman, Sylvie
AU - Russell, Nigel
AU - Craddock, Charles
AU - Mead, Adam
AU - Peniket, Andrew
AU - Porcher, Catherine
AU - Vyas, Paresh
N1 - © 2016 Quek et al.
PY - 2016/7/25
Y1 - 2016/7/25
N2 - 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.
AB - 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.
KW - Journal Article
U2 - 10.1084/jem.20151775
DO - 10.1084/jem.20151775
M3 - Article
C2 - 27377587
SN - 0022-1007
VL - 213
SP - 1513
EP - 1535
JO - The Journal of Experimental Medicine
JF - The Journal of Experimental Medicine
IS - 8
ER -