Genetically distinct leukemic stem cells in human CD34-acute myeloid leukemia are arrested at a hemopoietic precursor-like stage
| Autor: | Stephen Mackinnon, Charles Craddock, Sally Killick, Nigel H. Russell, Andrew Peniket, Adam Ivey, Catherine Garnett, Alexander Sternberg, David Grimwade, I-Jun Lau, Paul Virgo, Jessica Doondeea, Paresh Vyas, Andrew Carr, Lynn Quek, Dimitris Karamitros, Batchimeg Usukhbayar, Catherine Porcher, Rosemary E. Gale, Nicolas Goardon, Paul Cahalin, Bilyana Stoilova, Andrew Price, Hannah Hunter, Alison Kennedy, Georg W. Otto, Christopher Allen, Mike Griffiths, Benjamin Davies, Marlen Metzner, Ludovic Lhermitte, Sylvie D. Freeman, Adam J. Mead |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Myeloid Cellular differentiation Immunology Antigens CD34 Mice SCID Biology Article 03 medical and health sciences Mice 0302 clinical medicine Granulocyte-Macrophage Progenitor Cells Mice Inbred NOD hemic and lymphatic diseases medicine Immunology and Allergy Animals Humans Epigenetics Progenitor cell Research Articles Genetics Myeloid leukemia medicine.disease 3. Good health Cell biology Neoplasm Proteins Leukemia Haematopoiesis Leukemia Myeloid Acute 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Neoplastic Stem Cells Heterografts sense organs Stem cell Neoplasm Transplantation |
| Zdroj: | Quek, L, Otto, G W, Garnett, C, Lhermitte, L, Karamitros, D, Stoilova, B, Lau, I J, Doondeea, J, Doondeea, B, Kennedy, A, Metzner, M, Goardon, N, Ivey, A, Allen, C, Gale, R, Davies, B, Sternberg, A, Killick, S, Hunter, H, Cahalin, P, Price, A, Carr, A, Griffiths, M, Virgo, P, Mackinnon, S, Grimwade, D, Freeman, S, Russell, N, Craddock, C, Mead, A, Peniket, A, Porcher, C & Vyas, P 2016, ' Genetically distinct leukemic stem cells in human CD34-acute myeloid leukemia are arrested at a hemopoietic precursor-like stage ', The Journal of experimental medicine, vol. 213, no. 8, pp. 1513-1535 . https://doi.org/10.1084/jem.20151775 The Journal of Experimental Medicine |
| Popis: | Quek and colleagues identify human leukemic stem cells (LSCs) present in CD34− AML. In-depth characterization of the functional and clonal aspects of CD34− LSCs indicates that most are similar to myeloid precursors. 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. |
| Databáze: | OpenAIRE |
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