Ongoing Ig Gene Hypermutation in Salivary Gland Mucosa-Associated Lymphoid Tissue-Type Lymphomas

Abstract

Abstract Salivary gland mucosa-associated lymphoid tissue (MALT) type lymphomas are typically indolent B-cell neoplasms that are often associated with Sjogren's syndrome. To better define the cell of origin and evaluate whether antigen receptor stimulation may be playing a role in tumor growth, the Ig heavy and light chain variable genes (VH and VL) expressed by five salivary gland MALT lymphomas were cloned and sequenced. Comparison to known germline sequences indicated that three of the lymphoma VH genes were derived from 51p1, a member of the VH1 family, while the other two used different VH gene segments from the VH3 family, 22-2B and HG19. All five of the VL genes belonged to the VkIII family, with three derived from Humkv325 and the other two from the Vg and Humkv328 genes. Numerous point mutations relative to the proposed germline genes were present in all of the lymphoma VH and VL genes. In addition, the VH and VL genes from each lymphoma showed intraclonal sequence heterogeneity indicative of ongoing somatic hypermutation. Because the process of Ig gene hypermutation is thought to occur at the germinal center stage of B-cell development, these findings suggest the MALT lymphoma cell of origin may be a germinal center B cell. Selection against mutations that result in replacement of amino acids suggested that Ig stimulation may be important for lymphoma growth. The possibility that antigen receptor stimulation may be involved in the growth of salivary gland MALT lymphomas is further suggested by the noted restricted use of VH and VL gene segments.