Transcription of unrearranged Ig H chain genes in human B cell malignancies. Biased expression of genes encoded within the first duplication unit of the Ig H chain locus

Abstract

Analysis of the H chain class switch recombination events on the productive and nonproductive alleles of several human B cell lines has demonstrated that, in the majority of cases, the two loci had rearranged different CH genes. The absence of a strict correlation between the two rearrangement events has been interpreted in favor of a stochastic switching mechanism in human B cells. Based on the accessibility model for the H chain class switch, we have considered an alternative explanation, namely, that transcriptional activation of more than one CH gene could render more than one isotype accessible for recombination. In order to test this possibility, we have stimulated a number of IgM-bearing B cell tumors and analyzed the transcriptional response of their unrearranged C gamma and C alpha H chain genes at the Ig class level by Northern hybridization and at the subclass level by RNA-RNA solution hybridization. Our data show that human clonal B cell populations can simultaneously express germ-line transcripts of both gamma and alpha genes. Our data also demonstrate a bias in the expression of the different isotypes in the B cell chronic lymphocytic leukemias analyzed, with the genes present with the first duplication unit of the H chain locus (gamma 3, gamma 1, and alpha 1) being expressed almost exclusively. These findings indicate that transcriptional activation of large chromosomal regions containing more than one CH gene could render all the genes available for recombination and, therefore, provide an explanation for the asymmetry in the rearrangement events that have previously been described in human B cell tumors. The possible relevance of our findings to the molecular mechanism of the H chain class switch is discussed.