Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia.
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.
Somervaille
Tim C P
TC
Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA.
Cleary
Michael L
ML
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D018929:Cell Culture Techniques; D002461:Cell Line, Transformed; D019070:Cell Lineage; D002471:Cell Transformation, Neoplastic; D018920:Coculture Techniques; D017077:Culture Media, Conditioned; D004195:Disease Models, Animal; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D016130:Immunophenotyping; D007942:Leukemia, Experimental / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000473:pathology*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D013154:Spleen / Q000473:pathology; D014161:Transduction, Genetic; D014184:Transplantation, Homologous; D014965:X-Rays
D017077:Culture Media, Conditioned; D015514:Oncogene Proteins, Fusion; D019009:Proto-Oncogene Proteins c-kit