H3K79 methylation profiles define murine and human MLL-AF4 leukemias.
We created a mouse model wherein conditional expression of an Mll-AF4 fusion oncogene induces B precursor acute lymphoblastic (ALL) or acute myeloid leukemias (AML). Gene expression profile analysis of the ALL cells demonstrated significant overlap with human MLL-rearranged ALL. ChIP-chip analysis demonstrated histone H3 lysine 79 (H3K79) methylation profiles that correlated with Mll-AF4-associated gene expression profiles in murine ALLs and in human MLL-rearranged leukemias. Human MLL-rearranged ALLs could be distinguished from other ALLs by their H3K79 profiles, and suppression of the H3K79 methyltransferase DOT1L inhibited expression of critical MLL-AF4 target genes. We thus demonstrate that ectopic H3K79 methylation is a distinguishing feature of murine and human MLL-AF4 ALLs and is important for maintenance of MLL-AF4-driven gene expression.
Pubmed ID: 18977325 RIS Download
Animals | Cell Differentiation | Cells, Cultured | Chromatin Immunoprecipitation | Female | Flow Cytometry | Gene Expression Profiling | Gene Expression Regulation, Leukemic | Gene Rearrangement | Histone-Lysine N-Methyltransferase | Histones | Homeodomain Proteins | Humans | Immunophenotyping | Integrases | Leukemia, Myeloid, Acute | Lysine | Male | Methylation | Methyltransferases | Mice | Mice, Transgenic | Myeloid-Lymphoid Leukemia Protein | Oligonucleotide Array Sequence Analysis | Oncogene Proteins, Fusion | Precursor B-Cell Lymphoblastic Leukemia-Lymphoma | Principal Component Analysis | Protein Methyltransferases | RNA, Small Interfering | Transcription, Genetic | Tumor Markers, Biological