Conformational differences in the 3-D nanostructure of the immunoglobulin heavy-chain locust a hotspot of chromosomal translocations in B lymphocytes

Spectral precision distance microscopy was utilized to detect small but non etheless consistently present conformational differences between the immuno globulin heavy-chain gene clusters (IgH) that reside on the two chromosome 12 homologues in all diploid cells of the mouse. The euclidian distance (i. e.. the mean arithmetic three-dimensional [3-D] distance) between the 5 ' m ost IgH gene, C mu. and the 3 ' most IgH gene. C alpha. was used as the ind icator to define the co-presence of a condensed IgH domain and a relaxed Ig H domain in the same cell. In normal and malignant B cells in which IgH is actively rearranged and transcribed. the C mu /C alpha distance (genomic di stance similar to 180 kb) was found to range from 87.5 to 121 nm on the con densed IgH domain and from 154 to 207 nm on the relaxed IgH domain. In non- B cells (fibroblasts. neutrophils. and macrophages), in which IgH is inacti ve, the C mu /C alpha distance was found to range from 136 to 154 nm on the condensed IgH domain and from 250 to 292 nm on the related IgH domain. The se results suggested that conformational differences that may predispost: t he relaxed IgH domain for illegitimate genetic recombinations. such as chro mosomal translocations. are likely to exist in many cell types, including B cells. However. in B lymphocytes this structural predisposition may conspi re with the lineage-specific ability to activate proto-oncogenes (after jux taposition to IgH) to positively affect the preferential involvement of the relaxed IgH domain in chromosomal translocations. Additional studies are w arranted to validate this working hypothesis. (C) 2001 Elsevier Science Inc . All rights reserved.