The Molecular and Cellular Origins of Hodgkin's Disease

Hodgkin's disease is divulging its secrets at last. Despite the fact that Hodgkin's disease was the first lymphoma to be recognized as a distinct clinical entity (1), it has proved to be one of the most difficult lymphomas to approach molecularly. The clonal, malignant Hodgkin/Reed-Sternberg (H/RS) cells of Hodgkin's disease represent Ͻ 1% of the cells in an involved lymph node and are characteristically surrounded by a mixture of granulocytes, plasma cells, and T cells. Although several cell lines have been derived from patients with Hodgkin's disease, it has been difficult to prove, in most cases, that the cell lines are clonally related to the H/RS cells of the patients. Therefore, molecular approaches to the etiology and pathogenesis of Hodgkin's disease have relied on single cell micromanipulation of H/RS cells coupled with PCR amplification of RNA and genomic DNA. These techniques have shed considerable light on the cellular origins of Hodgkin's disease through analysis of the antigen receptor genes of H/RS cells (2). These techniques have also led to the identification of the first recurrent molecular abnormality of H/RS cells: mutations in the I ␬ B ␣ gene (3, 4; and, in this issue, Jungnickel et al. [5]). This finding specifically implicates the nuclear factor ␬ B (NF-␬ B) transcription factor signaling pathway in the pathogenesis of Hodgkin's disease. Once revealed, this association seems quite natural given the intense inflammatory component of Hodgkin's lymphoma lesions and the central role that NF-␬ B plays in the normal regulation of inflammatory responses (6). Cellular Origins of Hodgkin's Disease. The normal cellular counterpart of the H/RS cell has long been enigmatic due to the promiscuous expression in H/RS cells of markers that are normally expressed in distinct hematopoietic lineages. H/RS cells can variably express T cell markers Within the lymphoid lineages, the most lineage-specific molecular events involve rearrangement and mutation of the antigen receptor genes. Analysis of micromanipulated H/RS cells from nodular sclerosis Hodgkin's disease, the most common subtype, revealed that most patients had a clonal rearrangement of the V, D, and J segments of the IgH chain locus in the H/RS cells, indicating that these cells descended from B lymphocytes (2). Sequence analysis of the rearranged VDJ regions from these H/RS cells demonstrated a high load of somatic mutations, often resulting in nonfunctional Ig V regions (9). Inasmuch as somatic hyper-mutation of Ig genes occurs characteristically in germinal centers of secondary lymphoid …