In a model of immunoglobulin heavy‐chain (IGH)/MYCtranslocation, theIgh3′ regulatory region inducesMYCexpression at the immature stage of B cell development

Abstract

Reciprocal translocations involving the immunoglobulin loci and the cellular oncogene MYC are hallmark mutations of the human postgerminal center B cell neoplasm, Burkitt's lymphoma. They are occasionally found in other B cell lymphomas, as well. Translocations involving the heavy chain locus (IGH) place the MYC gene either in cis with both the intronic enhancer Emu and the IGH 3' regulatory region (3'RR) or in cis with only the 3'RR. The result is deregulated MYC expression. Recent studies have led to some controversy as to when, during B lymphocyte development, IGH/MYC chromosome translocations take place. A related issue, relevant not only to lymphoma development but also to normal controls on IGH gene expression, is the stage, during B lymphocyte development, at which the 3'RR is capable of activating MYC expression. We have developed mice transgenic for a human MYC (hMYC) gene under control of the four core enhancers from the mouse Igh 3'RR. Unlike other transgenic mouse models where premature and inappropriate MYC expression disrupts normal B cell development, the hMYC transgene in these studies carries a mutation that prohibits MYC protein synthesis. As a result, hMYC expression can be analyzed in all of the normal B cell compartments. Our data show that hMYC is expressed almost exclusively in B-lineage cells and is induced to high levels as soon as bone marrow cells reach the immature B cell stage.