title: Haploinsufficiency of Runx1/AML1 promotes myeloid features and leukaemogenesis in BXH2 mice.
abstract: Haploinsufficiency of RUNX1/AML1 is associated with familial platelet disorder with a predisposition to acute myeloid leukaemia (FPD/AML), but the causal relationship remains to be addressed experimentally. Mice heterozygous for the Runx1 null mutation, Runx1+/-, are considered to be genetically comparable with human FPD/AML patients but do not develop spontaneous leukaemia. To induce additional genetic alterations, retroviral insertional mutagenesis was employed with the use of BXH2 mice, which develop myeloid leukaemia because of the random integration of retrovirus present in the mouse. Heterozygous disruption of Runx1 in BXH2 mice resulted in a shortening of the latency period of leukaemia. In addition, BXH2-Runx1+/- mice exhibited more marked myeloid features than control mice. Moreover, the c-Kit gene, mutated in human RUNX leukaemias, was recurrently activated in BXH2-Runx1+/- mice, and a colony-forming assay revealed synergism between the Runx1+/- status and c-KIT overexpression. In conclusion, the BXH2-Runx1+/- system is a promising mouse model to investigate the mechanism of leukaemogenesis in FPD/AML.
authors.affiliation: Institute of Molecular and Cell Biology, Singapore.
authors.forename: Namiko
authors.initials: N
authors.lastname: Yamashita
authors.forename: Motomi
authors.initials: M
authors.lastname: Osato
authors.forename: Liqun
authors.initials: L
authors.lastname: Huang
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Yanagida
authors.forename: Scott C
authors.initials: SC
authors.lastname: Kogan
authors.forename: Masayuki
authors.initials: M
authors.lastname: Iwasaki
authors.forename: Takuro
authors.initials: T
authors.lastname: Nakamura
authors.forename: Katsuya
authors.initials: K
authors.lastname: Shigesada
authors.forename: Norio
authors.initials: N
authors.lastname: Asou
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ito
mesh_terms: D000818:Animals; D003114:Colony-Forming Units Assay; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D005822:Genetic Vectors; D006239:Haplotypes; D006801:Humans; D007951:Leukemia, Myeloid / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D016254:Mutagenesis, Insertional; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D016133:Polymerase Chain Reaction / Q000379:methods; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D009363:Neoplasm Proteins; C493726:Runx1 protein, mouse; D019009:Proto-Oncogene Proteins c-kit