Human acute myelogenous leukemia stem cells are rare and heterogeneous when assayed in NOD/SCID/IL2Rγc-deficient mice

Human leukemic stem cells, like other cancer stem cells, are hypothesized to be rare, capable of incomplete differentiation, and restricted to a phenotype associated with early hematopoietic progenitors or stem cells. However, recent work in other types of tumors has challenged the cancer stem cell...

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Bibliographic Details
Published in:The Journal of clinical investigation 2011-01, Vol.121 (1), p.384
Main Authors: Sarry, Jean-Emmanuel, Murphy, Kathleen, Perry, Robin, Sanchez, Patricia V, Secreto, Anthony, Keefer, Cathy, Swider, Cezary R, Strzelecki, Anne-Claire, Cavelier, Cindy, Recher, Christian, Mansat-De, Veronique, Delabesse, Eric, Danet-Desnoyers, G, Carroll, Martin
Format: Article
Language:English
Subjects:
Glycoproteins
Physiological aspects
Stem cells
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Summary:Human leukemic stem cells, like other cancer stem cells, are hypothesized to be rare, capable of incomplete differentiation, and restricted to a phenotype associated with early hematopoietic progenitors or stem cells. However, recent work in other types of tumors has challenged the cancer stem cell model. Using a robust model of xenotransplantation based on NOD/SCID/IL2Rγc-deficient mice, we confirmed that human leukemic stem cells, functionally defined by us as SCID leukemia-initiating cells (SL-ICs), are rare in acute myelogenous leukemia (AML). In contrast to previous results, SL-ICs were found among cells expressing lineage markers (i.e., among Lin+ cells), CD38, or CD45RA, all markers associated with normal committed progenitors. Remarkably, each engrafting fraction consistently recapitulated the original phenotypic diversity of the primary AML specimen and contained self-renewing leukemic stem cells, as demonstrated by secondary transplants. While SL-ICs were enriched in the [Lin.sup.-][CD38.sup.-] fraction compared with the other fractions analyzed, SL-ICs in this fraction represented only one-third of all SL-ICs present in the unfractionated specimen. These results indicate that human AML stem cells are rare and enriched but not restricted to the phenotype associated with normal primitive hematopoietic cells. These results suggest a plasticity of the cancer stem cell phenotype that we believe has not been previously described.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI41495.