Quek, L;
Otto, GW;
Garnett, C;
Lhermitte, L;
Karamitros, D;
Stoilova, B;
Lau, I-J;
... Vyas, P; + view all
(2016)
Genetically distinct leukemic stem cells in human CD34(-) acute myeloid leukemia are arrested at a hemopoietic precursor-like stage.
Journal of Experimental Medicine
, 213
(8)
pp. 1513-1535.
10.1084/jem.20151775.
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Abstract
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.
| Type: | Article |
|---|---|
| Title: | Genetically distinct leukemic stem cells in human CD34(-) acute myeloid leukemia are arrested at a hemopoietic precursor-like stage |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1084/jem.20151775 |
| Publisher version: | http://dx.doi.org/10.1084/jem.20151775 |
| Language: | English |
| Additional information: | © 2016 Quek et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http ://www .rupress .org /terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial– Share Alike 3.0 Unported license, as described at http ://creativecommons .org /licenses /by -nc -sa /3 .0 /). |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Immunology, Medicine, Research & Experimental, Research & Experimental Medicine, Minimal Residual Disease, Acute Myelogenous Leukemia, Polymerase-Chain-Reaction, Clonal Hematopoiesis, Cytoplasmic Nucleophosmin, Initiating Cells, Bone-Marrow, In-Vivo, Progenitors, Mutations |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1504668 |
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