Haploinsufficiency of Runx1/AML1 promotes myeloid features and leukaemogenesis in BXH2 mice.
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.
Yamashita
Namiko
N
Institute of Molecular and Cell Biology, Singapore.
Osato
Motomi
M
Huang
Liqun
L
Yanagida
Masatoshi
M
Kogan
Scott C
SC
Iwasaki
Masayuki
M
Nakamura
Takuro
T
Shigesada
Katsuya
K
Asou
Norio
N
Ito
Yoshiaki
Y
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
D050676:Core Binding Factor Alpha 2 Subunit; D009363:Neoplasm Proteins; C493726:Runx1 protein, mouse; D019009:Proto-Oncogene Proteins c-kit