Abstract
Using a mouse model of human acute myeloid leukemia (AML) induced by the MLL-AF9 oncogene, we demonstrate that colony-forming cells (CFCs) in the bone marrow and spleen of leukemic mice are also leukemia stem cells (LSCs). These self-renewing cells (1) are frequent, accounting for 25%-30% of myeloid lineage cells at late-stage disease; (2) generate a phenotypic, morphologic, and functional leukemia cell hierarchy; (3) express mature myeloid lineage-specific antigens; and (4) exhibit altered microenvironmental interactions by comparison with the oncogene-immortalized CFCs that initiated the disease. Therefore, the LSCs responsible for sustaining, expanding, and regenerating MLL-AF9 AML are downstream myeloid lineage cells, which have acquired an aberrant Hox-associated self-renewal program as well as other biologic features of hematopoietic stem cells.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bone Marrow Cells / cytology
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Cell Culture Techniques
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Cell Line, Transformed
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Cell Lineage
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Cell Transformation, Neoplastic
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Coculture Techniques
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Culture Media, Conditioned
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Disease Models, Animal
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Hematopoietic Stem Cell Transplantation
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Hematopoietic Stem Cells / metabolism
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Hematopoietic Stem Cells / pathology*
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Humans
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Immunophenotyping
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Leukemia, Experimental / etiology
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Leukemia, Experimental / genetics
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Leukemia, Experimental / pathology*
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Leukemia, Myeloid, Acute / blood
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Leukemia, Myeloid, Acute / genetics*
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Leukemia, Myeloid, Acute / pathology
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Mice
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Mice, Inbred C57BL
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Mice, Inbred Strains
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Mice, Transgenic
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Myeloid Cells / pathology*
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism*
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Proto-Oncogene Proteins c-kit / metabolism
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Retroviridae / genetics
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Spleen / pathology
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Transduction, Genetic
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Transplantation, Homologous
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X-Rays
Substances
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Culture Media, Conditioned
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Oncogene Proteins, Fusion
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Proto-Oncogene Proteins c-kit