The pathogenesis of AIDS-related nonHodgkin lymphomas (AIDS-NHLs

No abstract

Summary. Plasmablastic lymphoma (PBL) of the oral cavity is an aggressive B-cell lymphoma associated with human immunodeficiency virus infection. Although the lymphoma phenotype is consistent with late B-cell maturation, the molecular histogenesis of PBL is unknown. We investigated PBL of the oral cavity (n ¼ 12) for mutations of immunoglobulin variable heavy chain (IgV H ) and BCL-6 genes, which are acquired by B cells at the time of germinal centre (GC) transit, and for expression of BCL-6, MUM-1 and CD138, which distinguish GC B cells from post-GC B cells. Somatic IgV H hypermutation occurred in 4/10 PBL whereas 6/10 PBL displayed germline IgV H genes. Among PBL carrying hypermutated IgV H genes, the pattern of IgV H mutations was consistent with antigen stimulation in two cases. Mutations of the BCL-6 gene were restricted to 1/12 patients with PBL of the oral cavity. All cases of PBL of the oral cavity displayed the BCL-6 -/MUM-1 + /CD138 + phenotype that is consistent with late stage of B-cell differentiation. Overall, these data indicate that, despite a common phenotype and an apparently similar degree of differentiation, PBL of the oral cavity are characterized by histogenetic heterogeneity. A subset of PBL of the oral cavity carried the molecular clues of GC transit and conceivably originated from a B-cell subset corresponding to post-GC B cells. Conversely, another fraction of these lymphomas were devoid of somatic IgV H mutations and appeared to originate from naive B cells that have undergone preterminal differentiation independent of GC transit.

Recognition of biased immunoglobulin variable (IgV) gene usage in B-cell chronic lymphocytic leukemia (B-CLL) may yield insight into leukemogenesis and may help to refine prognostic categories. We explored Ig variable heavy (V H ) and light (V L ) chain gene usage in highly stable and indolent B-CLL (n ¼ 25) who never required treatment over 10 or more years. We observed an unexpectedly high usage of mutated V H 3-72 (6/25; 24.0%), a gene that was otherwise rare in B-CLL (7/805; 0.87%; Po0.01), including mutated cases (6/432; 1.39%; Po0.01) and was exceptional among indolent (1/230, 0.435%; Po0.01), and aggressive B-cell lymphomas (0/105; Po0.01). Three of six V H 3-72 B-CLL cases utilized the same V L V j 4-1 gene. Two V H 3-72 B-CLL cases had highly homologous V H complementarity determining regions 3 (CDR3s), encoding Cys-XXXX-Cys domains, and utilized V j 4-1 genes with homologous IgV L CDR3s. An identical threonine to isoleucine change at codon 84 of V H 3-72 framework region 3 (FR3) recurred in four cases of highly stable V H 3-72 B-CLL. This mutation is expected to cause a conformational change of FR3 proximal to CDR3 that might critically affect high-affinity antigen binding. B-cell receptors encoded by V H 3-72 may identify a specific B-CLL group and be implicated in leukemogenesis through an antigen-driven expansion of B cells.

Summary. Aberrant promoter hypermethylation is a mechanism of tumour suppressor gene inactivation. We explored aberrant promoter hypermethylation of multiple genes in 88 human immunodeficiency virus (HIV)-non Hodgkin lymphomas (NHL), 25 post-transplant lymphoproliferative disorders (PTLD) and five common variable immunodeficiency (CVI)-related NHL. Twenty-six of 79 (32AE9%) HIV-NHL, eight of 14 (57AE1%) PTLD and two of five (40AE0%) CVI-NHL showed aberrant hypermethylation of O 6 -methylguanine-DNA methyltransferase (MGMT). Aberrant hypermethylation of death-associated protein-kinase (DAP-K) occurred in 70 of 84 (83AE3%) HIV-NHL, 19 of 25 (72AE0%) PTLD and three of five (60AE0%) CVI-NHL. These data implicate MGMT and DAP-K hypermethylation in lymphomagenesis of immunodeficient hosts. In particular, promoter hypermethylation of DAP-K represents the most frequent molecular alteration yet identified in immunodeficiency-related lymphomas.