Modeling the initiation and progression of human acute leukemia in mice.
Our understanding of leukemia development and progression has been hampered by the lack of in vivo models in which disease is initiated from primary human hematopoietic cells. We showed that upon transplantation into immunodeficient mice, primitive human hematopoietic cells expressing a mixed-lineage leukemia (MLL) fusion gene generated myeloid or lymphoid acute leukemias, with features that recapitulated human diseases. Analysis of serially transplanted mice revealed that the disease is sustained by leukemia-initiating cells (L-ICs) that have evolved over time from a primitive cell type with a germline immunoglobulin heavy chain (IgH) gene configuration to a cell type containing rearranged IgH genes. The L-ICs retained both myeloid and lymphoid lineage potential and remained responsive to microenvironmental cues. The properties of these cells provide a biological basis for several clinical hallmarks of MLL leukemias.
Barabé
Frédéric
F
Division of Cell and Molecular Biology, University Health Network, Toronto, Ontario, M5G 1L7, Canada.
Kennedy
James A
JA
Hope
Kristin J
KJ
Dick
John E
JE
D000818:Animals; D016026:Bone Marrow Transplantation; D002471:Cell Transformation, Neoplastic; D004195:Disease Models, Animal; D018450:Disease Progression; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D005803:Genes, Immunoglobulin; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007945:Leukemia, Lymphoid / Q000473:pathology / Q000503:physiopathology; D007951:Leukemia, Myeloid / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
D007143:Immunoglobulin Heavy Chains; C474558:MLL-AF9 fusion protein, human; C425207:MLL-ENL oncoprotein, human; D015514:Oncogene Proteins, Fusion; D051788:Myeloid-Lymphoid Leukemia Protein