Breakpoints of t(4;11) translocations in the human MLL and AF4 genes in ALL patients are preferentially clustered outside of high-affinity matrix attachment regions

• Published in: Journal of cellular biochemistry Vol. 82; no. 2; pp. 299 - 309
• Main Authors: Hensel, Jan Patrick, Gillert, Esther, Fey, Georg H., Marschalek, Rolf
• Format: Journal Article
• Language: English
• Published: New York John Wiley & Sons, Inc 01.01.2001
• Subjects: 11; AF4 gene; Chromosome Breakage; Chromosome Mapping; Chromosomes, Human, Pair 11 - genetics; Chromosomes, Human, Pair 11 - ultrastructure; Chromosomes, Human, Pair 4 - genetics; Chromosomes, Human, Pair 4 - ultrastructure; Contig Mapping; DNA, Complementary - genetics; DNA, Neoplasm - genetics; DNA, Neoplasm - metabolism; Humans; leukemia chromosomal translocation t; leukemia chromosomal translocation t(4;11); MLL gene; Myeloid-Lymphoid Leukemia Protein; Nuclear Matrix - metabolism; Oncogene Proteins, Fusion - genetics; Polymerase Chain Reaction; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Recombination, Genetic; SAR/MAR elements; Translocation, Genetic - genetics
• ISSN: 0730-2312; 1097-4644
• DOI: 10.1002/jcb.1161

Chromosomal translocations t(4;11) are based on illegitimate recombinations between the human MLL and AF4 genes, and are associated with high‐risk acute leukemias of infants and young children. Here, the question was asked, whether a correlation exists between the location of translocation breakpoints within both genes and the location of S/MARs. In “halo mapping experiments” (to define SARs), about 20 kb of MLL DNA was found to be attached to the nuclear matrix. Similar experiments performed for the translocation partner gene AF4 revealed that SARs are spanning nearly the complete breakpoint cluster region of the AF4 gene. By using short DNA fragments in “scaffold reassociation experiments” (to define MARs), similar results were obtained for both genes. However, Distamycin A competition experiments in combination with “scaffold reassociation experiments” revealed specific differences in the affinity of each tested DNA fragment to bind the isolated nuclear matrix proteins. When the latter data were compared with the known location of chromosomal breakpoints for both genes, an unexpected correlation was observed. DNA areas with strong MAR affinity contained fewer translocation breakpoints, while areas with weak or absent MAR affinity showed a higher density of chromosomal breakpoints. J. Cell. Biochem. 82: 299–309, 2001. © 2001 Wiley‐Liss, Inc.