The Leukemia and Lymphoma Molecular Profiling Project recently published results from DNA microarray analyses of 240 diffuse large B-cell lymphomas (DLBCLs). Four gene expression "signatures" were identified as correlated with patient outcome, including the major histocompatibility complex (MHC) class II genes (eg, HLA-DRA) which correlated with better survival. We further analyzed the effects of HLA-DRA on survival and correlated gene expression with protein status and tumor-infiltrating lymphocytes. The 5-year overall survival was 24% in the lowest 10% of HLA-DRA expression, 37% in the 10% to 25% group, 50% in the 25% to 50% group, and 55% for patients in the highest 50%. Further analysis demonstrated that the hazard ratio of death was a nonlinear function of HLA-DRA expression. Adjustment for the International Prognostic Index did not alter the impact of HLA-DRA on survival. Other MHC class II genes were found to predict survival similarly.
IntroductionDiffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma diagnosed in the United States, accounting for approximately 40% of non-Hodgkin lymphoma (NHL) overall. Patients with DLBCL have an extremely variable clinical outcome using standard adriamycin-containing chemotherapy, ranging from cure to treatment failure, relapse, and death. While the median survival for all patients treated with such regimens is approximately 4 years, survival can range from a few weeks to more than 10 years when the disease is cured. This variability in clinical outcome suggests marked intertumoral heterogeneity. This heterogeneity is reflected, to a limited extent, by the morphologic classification of DLBCL, which has recently evolved to include several subtypes. The new World Health Organization (WHO) classification scheme published in 2001 identifies several morphologic and immunophenotypic variants, including centroblastic, immunoblastic, T-cell/ histiocyte-rich, anaplastic, plasmablastic, and DLBCL with expression of full-length anaplastic lymphoma kinase (ALK). 1 However, even within these defined subtypes, considerable variation in clinical outcome persists, indicating that additional factors are relevant.The major histocompatibility complex (MHC) on chromosome 6p encodes a series of proteins responsible for elicitation of a cellular immune response. MHC class I proteins (human leukocyte antigen-A [HLA-A], HLA-B, and HLA-C) are expressed on all nucleated cells and function in the presentation of antigenic peptides to CD8 ϩ cytotoxic T cells. MHC class II proteins are expressed only on professional antigen-presenting cells such as B lymphocytes, monocytes, and dendritic cells. Class II proteins function in the presentation of antigenic peptides to CD4 ϩ helper T cells. There are 3 classical MHC class II proteins, HLA-DR, HLA-DQ, HLA-DP, and 2 nonclassical molecules, HLA-DM and HLA-DO. Each protein is a heterodimer of an alpha and a beta chain, encoded by the A and B genes, respectively. The classical proteins reside on the cell surface and compose the antig...