Increased dosage of Runx1/AML1 acts as a positive modulator of myeloid leukemogenesis in BXH2 mice.
The RUNX1/AML1 gene on chromosome 21 is most frequently inactivated in human leukemias. In addition, an increased dose of RUNX1 is suggested as a basis for several kinds of leukemias. Amplifications of chromosome 21 or the RUNX1 gene are shown to be associated with leukemias with lymphoid lineage, whereas its involvement in myeloid lineage remains unclear. In this study, we generated GATA-1 promoter-driven Runx1 transgenic (Tg) mice, which showed a transient mild increase of megakaryocyte marker-positive myeloid cells but no spontaneous leukemia. These mice were then crossed with BXH2 mice, which have a replication-competent retrovirus in the mouse and develop myeloid leukemia due to insertional mutagenesis by random integration of the virus. Overexpressed Runx1 transgene in BXH2 mice resulted in shortening of the latency of leukemia with increased frequency of megakaryoblastic leukemia, suggesting that increased Runx1 dosage is leukemogenic in myeloid lineage. Identifications of retroviral integration sites revealed the genetic alterations that may cooperate with Runx1 overdose in myeloid leukemogenesis. This mouse model may be useful for analysing the pathogenesis of myeloid leukemias with RUNX1 overdose, especially to examine whether an extra-copy of RUNX1 by trisomy 21 is causally related to Down's syndrome-related acute megakaryoblastic leukemia (DS-AMKL).
Yanagida
Masatoshi
M
Institute of Molecular and Cell Biology, Singapore.
Osato
Motomi
M
Yamashita
Namiko
N
Liqun
Huang
H
Jacob
Bindya
B
Wu
Feng
F
Cao
Xinmin
X
Nakamura
Takuro
T
Yokomizo
Tomomasa
T
Takahashi
Satoru
S
Yamamoto
Masayuki
M
Shigesada
Katsuya
K
Ito
Yoshiaki
Y
D000818:Animals; D050676:Core Binding Factor Alpha 2 Subunit; D004251:DNA Transposable Elements; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; D018628:Gene Dosage; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D039661:Integrin beta3 / Q000235:genetics / Q000276:immunology; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000473:pathology; D007962:Leukocytes / Q000276:immunology / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
D050676:Core Binding Factor Alpha 2 Subunit; D004251:DNA Transposable Elements; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; C494689:Gata1 protein, mouse; D039661:Integrin beta3; D011518:Proto-Oncogene Proteins; C493728:RUNX1 protein, human; C493726:Runx1 protein, mouse; D014157:Transcription Factors