The topological organization of chromosomes 9 and 22 in cell nuclei has a determinative role in the induction of t(9,22) translocations and in the pathogenesis of t(9,22) leukemias

Abstract.

The neighborhood relationships of chromosomes can be of great importance for basic cellular processes such as gene expression or translocation induction. In this study, the topological organization of chromosomes 9 and 22 was investigated in cell nuclei of G0-phase lymphocytes. We found that the territories of both chromosomes are predominantly located in the central region of cell nuclei. In addition to this, chromosomes 9 and 22 were frequently associated in pairs detected as false-positive ABL-BCR fusions. Both effects might substantially increase the probability of interaction between chromosomes. Because of this, exchange aberrations were studied in chromosomes 9 and 22 of human lymphocytes irradiated by neutrons. The rate of aberration induction between these chromosomes was 11 times higher than the expected frequency based on the fractional molecular weight of these chromosomes. We show that the increased rate of exchange between chromosomes 9 and 22 induced by neutrons corresponds to the neighborhood relationships of both chromosomes. Similar topological characteristics of ABL and BCR genes were found in several cell lines: T- and B-lymphocytes, HL60 cells and bone marrow cells. This finding suggests that the specific chromatin structure mentioned might be responsible for the high rate of induction of t(9;22)-positive leukemias in the human population.