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.

The significance of telomeric aggregates in the interphase nuclei of tumor cells

“…Chromosomes 9 and 22 are in close enough proximity to permit this translocation. This finding is supported by Kozubek et al [1999] who state that the positions of chromosomes 9 and 22 have a determinative role in the induction of t(9;22) and in the development of t(9;22) leukemias. For mouse B cells, chromosomes 12 and 15 are found in a close neighborhood in lymphocytes (where they are involved in balanced translocations in mouse plasmacytoma) but are found more distant in mouse hepatocytes [Parada et al, 2004].…”

The role of nuclear organization in cancer

“…Furthermore, the frequency of observed recurrent gene fusions arising from translocations in cancer cells correlates with the frequency of side-by-side pairing of the relevant genes in normal control cells. These include BCR and ABL (fused in chronic myeloid leukaemia); PML and RARA (acute promyelocytic leukaemia); MYC and IGH, IGK or IGL (B cell leukaemia/lymphoma); IGH and CCND1, BCL2 or BCL6 (B cell leukaemia/lymphoma) [43][44][45][46][47][48].…”

Spatial genome organization in the formation of chromosomal translocations

“…This appears to be the case. The t(9;22)(q34;q11) translocation in chronic myeloid leukemia results in the fusion of BCR and ABL and these genes are in closer spatial proximity in normal heamatopoetic cells than other, non-translocating gene pairs [104][105][106]115,116]. Significantly, exposure to radiation, a known inducer of leukemia, results in BCR and ABL locating nearer to each other, in a more central part of the nucleus [104,105].…”