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Science 27 April 2007:
Vol. 316. no. 5824, pp. 600 - 604
DOI: 10.1126/science.1139851
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Reports

Modeling the Initiation and Progression of Human Acute Leukemia in Mice

Frédéric Barabé,1,2,3,4* James A. Kennedy,1,5* Kristin J. Hope,1,5 John E. Dick1,5{dagger}

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.

1 Division of Cell and Molecular Biology, University Health Network, Toronto, Ontario, M5G 1L7, Canada.
2 Department of Medicine, Laval University, Québec, G1K 7P4, Canada.
3 Department of Hematology, Enfant-Jesus Hospital, Qué-bec, G1J 1Z4, Canada.
4 Research Center in Infectious Diseases, Centre Hospitalier Universitaire de Québec–Centre Hospitalier de l'Université Laval, Québec, G1V 4G2, Canada.
5 Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, Canada.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: jdick{at}uhnres.utoronto.ca

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Science. ISSN 0036-8075 (print), 1095-9203 (online)