title: Human chromosomal translocations at CpG sites and a theoretical basis for their lineage and stage specificity.
abstract: We have assembled, annotated, and analyzed a database of over 1700 breakpoints from the most common chromosomal rearrangements in human leukemias and lymphomas. Using this database, we show that although the CpG dinucleotide constitutes only 1% of the human genome, it accounts for 40%-70% of breakpoints at pro-B/pre-B stage translocation regions-specifically, those near the bcl-2, bcl-1, and E2A genes. We do not observe CpG hotspots in rearrangements involving lymphoid-myeloid progenitors, mature B cells, or T cells. The stage specificity, lineage specificity, CpG targeting, and unique breakpoint distributions at these cluster regions may be explained by a lesion-specific double-strand breakage mechanism involving the RAG complex acting at AID-deaminated methyl-CpGs.
authors.affiliation: Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, 1441 Eastlake Avenue, MC9176, Los Angeles, CA 90089-9176, USA.
authors.forename: Albert G
authors.initials: AG
authors.lastname: Tsai
authors.forename: Haihui
authors.initials: H
authors.lastname: Lu
authors.forename: Sathees C
authors.initials: SC
authors.lastname: Raghavan
authors.forename: Markus
authors.initials: M
authors.lastname: Muschen
authors.forename: Chih-Lin
authors.initials: CL
authors.lastname: Hsieh
authors.forename: Michael R
authors.initials: MR
authors.lastname: Lieber
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D019457:Chromosome Breakage; D018899:CpG Islands; D003564:Cytidine Deaminase / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D019940:Genes, bcl-1; D019254:Genes, bcl-2; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007945:Leukemia, Lymphoid / Q000235:genetics* / Q000378:metabolism; D014178:Translocation, Genetic; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D003564:Cytidine Deaminase; D018398:Homeodomain Proteins; D000098830:AICDA (Activation-Induced Cytidine Deaminase); C407909:TCF3 protein, human; C064658:RAG-1 protein