DOI: 10.1126/science.1139851 , 600 (2007); 316Science et al.Frédéric Barabé,Acute Leukemia in MiceModeling the Initiation and Progression of Human www.sciencemag.org (this information is current as of October 1, 2007 ):The following resources related to this article are available online at http://www.sciencemag.org/cgi/content/full/316/5824/600version of this article at: including high-resolution figures, can be found in the onlineUpdated information and services, http://www.sciencemag.org/cgi/content/full/316/5824/600/DC1 can be found at: Supporting Online Material http://www.sciencemag.org/cgi/content/full/316/5824/600#otherarticles, 9 of which can be accessed for free: cites 25 articlesThis article 1 article(s) on the ISI Web of Science. cited byThis article has been http://www.sciencemag.org/cgi/collection/medicineMedicine, Diseases : subject collectionsThis article appears in the following http://www.sciencemag.org/about/permissions.dtl in whole or in part can be found at: this articlepermission to reproduce of this article or about obtaining reprintsInformation about obtaining registered trademark of AAAS. is aScience2007 by the American Association for the Advancement of Science; all rights reserved. The title CopyrightAmerican Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by theScience on October 1, 2007 www.sciencemag.orgDownloaded fromsion in transheterozygous females, is illustratedin Fig. 2, E and F.Our data show de novo s ynthesis of a se lfishgenetic element able to drive itself into apopulation. This laboratory demonstration not-withstanding, several obstacles remain to theimplementation of Medea-based populationreplacement in the wild. First, for pests such asmosquito species, there is little genetic ormolecular information regarding genes and pro-moters used during oogenesis and early embr yo-genesis. This information is straightforward togenerate, w ith the use of transcriptional profilingto identify appropriately expressed genes andtransgenesis and RNA interference in adultfemales to identify th ose required for embryon icdevelopment, but it remains to be acquired. Inaddition, current models of the sp read of Medeado not take into account important real-worldvariables, such as migration, nonrandom mating,and the fact that importa nt disease vectors such asAnopheles gambiae consist of multiple partiallyreproductively isolated strains (20, 21). Althoughan understanding of th e above issu es is critical forthe success of any population-replacement strat-egy, the problems are not intractable, as evidencedby past successes in controlling pests by means ofsterile-male release (18) and as implied by ourgrowing understanding of mosquito populationgenetics, immunity, and ecology (20–23).References and Notes1. M. d e Lara Capurro et al., Am. J. Trop. Med. Hyg. 62, 427(2000).2. J. Ito, A. 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Kambris et al., EMBO Rep. 4, 64 (2003).18. F. Gould, P. Schliekelman, Annu. Rev. Entomol. 49, 193(2004).19. B. W. Geer, M. M. Green, Am. Nat. 96, 175 (1962).20. A. della Torre et al., Science 298, 115 (2002).21. M. Coetzee, Am. J. Trop. Med. Hyg. 70, 103 (2004).22. D. Vlachou, F. C. Kafotis, Curr. Opin. Microbiol. 8, 415(2005).23. H. Pates, C. Curtis, Annu. Rev. En tomol. 50,53(2005).24. D. D. Nimmo, L. Alphey, J. M. Meredith, P. Eggleston,Insect Mol. Biol. 15, 129 (2006).25. This work did not receive specific funding. It wassupported by NIH grants GM057422 and GM70956 toB.A.H. and NS042580 and NS048396 to M.G. C.-H.C. wassupported by the Moore Foundation Center for BiologicalCircuit Design. We thank two reviewers for usefulcomments and improvements on the manuscript.GenBank accession numbers for Medeamyd88andMedeamyd88-intare EF447106 and EF447105, respectively.Supporting Online Materialwww.sciencemag.org/cgi/content/full/1138595/DC1Materials and MethodsFigs. S1 to S5References8 December 2006; accepted 20 March 2007Published online 29 March 2007;10.1126/science.1138595Include this informati on when citing this paper.Modeling the Initiation andProgression of Human AcuteLeukemia in MiceFrédéric Barabé,1,2,3,4* James A. Kennedy,1,5* Kristin J. Hope,1,5John E. Dick1,5†Our understanding of leukemia development and progression has been hampered by the lack of invivo models in which disease is initiated from primary human hematopoietic cells. We showed thatupon transplantation into immunodeficient mice, primitive human hematopoietic cells expressing amixed-lineage leukemia (MLL) fusion gene generated myeloid or lymphoid acute leukemias, withfeatures that recapitulated human diseases. Analysis of serially transplanted mice revealed that thedisease is sustained by leukemia-initiating cells (L-ICs) that have evolved over time from a primitivecell type with a germline immunoglobulin heavy chain (IgH) gene configuration to a cell typecontaining rearranged IgH genes. The L-ICs retained both myeloid and lymphoid lineage potentialand remained responsive to microenvironmental cues. The properties of these cells provide abiological basis for several clinical hallmarks of MLL leukemias.In hu man leukemia, only a su bset of leu-kemic blast cells have the potential to initiateand recapitulate disease when transplantedinto immunodeficient mice (1–3). To date, theseapproaches have not permitted identification ofthe cell type(s) from which leukemia- initiatingcells (L-ICs) originate or assessment of how