Identification of genes that synergize with Cbfb-MYH11 in the pathogenesis of acute myeloid leukemia
Biochemistry & Molecular Pharmacology
Graduate School of Biomedical Sciences; Program in Gene Function and Expression; Department of Neurobiology
Medical Subject Headings
Acute Disease; Animals; Artificial Gene Fusion; Base Sequence; Blotting, Southern; Core Binding Factor Alpha 1 Subunit; Core Binding Factor beta Subunit; DNA Primers; DNA-Binding Proteins; Leukemia, Myeloid; Mice; Molecular Sequence Data; NIH 3T3 Cells; Polymerase Chain Reaction; Retroviridae; Transcription Factor AP-2; Transcription Factors
Life Sciences | Medicine and Health Sciences
Acute myeloid leukemia subtype M4 with eosinophilia is associated with a chromosome 16 inversion that creates a fusion gene CBFB-MYH11. We have previously shown that CBFB-MYH11 is necessary but not sufficient for leukemogenesis. Here, we report the identification of genes that specifically cooperate with CBFB-MYH11 in leukemogenesis. Neonatal injection of Cbfb-MYH11 knock-in chimeric mice with retrovirus 4070A led to the development of acute myeloid leukemia in 2-5 months. Each leukemia sample contained one or a few viral insertions, suggesting that alteration of one gene could be sufficient to synergize with Cbfb-MYH11. The chromosomal position of 67 independent retroviral insertion sites (RISs) was determined, and 90% of the RISs mapped within 10 kb of a flanking gene. In total, 54 candidate genes were identified; six of them were common insertion sites (CISs). CIS genes included members of a zinc finger transcription factors family, Plag1 and Plagl2, with eight and two independent insertions, respectively. CIS genes also included Runx2, Myb, H2T24, and D6Mm5e. Comparison of the remaining 48 genes with single insertion sites with known leukemia-associated RISs indicated that 18 coincide with known RISs. To our knowledge, this retroviral genetic screen is the first to identify genes that cooperate with a fusion gene important for human myeloid leukemia.
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Citation: Proc Natl Acad Sci U S A. 2004 Apr 6;101(14):4924-9. Epub 2004 Mar 24. Link to article on publisher's site
DOI of Published Version
Proceedings of the National Academy of Sciences of the United States of America
Castilla, Lucio H.; Perrat, Paola N.; Martinez, Natalia Julia; Landrette, Sean F.; Keys, R.; Oikemus, Sarah R.; Flanegan, J.; Heilman, Susan Ann; Garrett, Lisa; Dutra, A.; Anderson, S.; Pihan, German A.; Wolff, L.; and Liu, Pu P., "Identification of genes that synergize with Cbfb-MYH11 in the pathogenesis of acute myeloid leukemia" (2004). GSBS Student Publications. 188.