Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell.
On the subject of acute myeloid leukemia (AML), there is little consensus about the target cell within the hematopoietic stem cell hierarchy that is susceptible to leukemic transformation, or about the mechanism that underlies the phenotypic, genotypic and clinical heterogeneity. Here we demonstrate that the cell capable of initiating human AML in non-obese diabetic mice with severe combined immunodeficiency disease (NOD/SCID mice) - termed the SCID leukemia-initiating cell, or SL-IC - possesses the differentiative and proliferative capacities and the potential for self-renewal expected of a leukemic stem cell. The SL-ICs from all subtypes of AML analyzed, regardless of the heterogeneity in maturation characteristics of the leukemic blasts, were exclusively CD34++ CD38-, similar to the cell-surface phenotype of normal SCID-repopulating cells, suggesting that normal primitive cells, rather than committed progenitor cells, are the target for leukemic transformation. The SL-ICs were able to differentiate in vivo into leukemic blasts, indicating that the leukemic clone is organized as a hierarchy.
Bonnet
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Department of Genetics, Research Institute, Hospital for Sick Children, University of Toronto, Ontario, Canada.
Dick
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JE
D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000208:Acute Disease; D000368:Aged; D000818:Animals; D015703:Antigens, CD; D018952:Antigens, CD34; D000943:Antigens, Differentiation; D002454:Cell Differentiation; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D002999:Clone Cells; D004195:Disease Models, Animal; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D006801:Humans; D016130:Immunophenotyping; D007948:Leukemia, Monocytic, Acute / Q000473:pathology*; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D015479:Leukemia, Myelomonocytic, Acute / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009699:N-Glycosyl Hydrolases; D009368:Neoplasm Transplantation
D015703:Antigens, CD; D018952:Antigens, CD34; D000943:Antigens, Differentiation; D008562:Membrane Glycoproteins; D009699:N-Glycosyl Hydrolases; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; C498155:Cd38 protein, mouse; D051997:ADP-ribosyl Cyclase 1