Variable Region Gene Analysis of an Isotype-Switched (IgA) Variant of Chronic Lymphocytic Leukemia

• Published in: Blood 1992-11, Vol.80 (9), p.2287-2297
• Main Authors: Friedman, David F., Moore, Jonni S., Erikson, Jan, Manz, Joanna, Goldman, June, Nowell, Peter C., Silberstein, Leslie E.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Base Sequence; Biological and medical sciences; Blotting, Southern; Cardiolipins - immunology; Cloning, Molecular; DNA, Neoplasm - blood; DNA, Neoplasm - genetics; DNA, Neoplasm - isolation & purification; Enzyme-Linked Immunosorbent Assay; Genes, Immunoglobulin; Genetic Variation; Hematologic and hematopoietic diseases; Humans; Hybridomas - immunology; Immunoglobulin A - genetics; Immunoglobulin A - isolation & purification; Immunoglobulin Heavy Chains - genetics; Immunoglobulin Variable Region - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - immunology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Molecular Sequence Data; Monocytes - physiology; Oligodeoxyribonucleotides
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V80.9.2287.2287

Chronic lymphocytic leukemia of B-cell origin (B-CLL) is generally thought to arise by neoplastic transformation of B lymphocytes, which express CD5 and have features of an early stage of B-cell differentiation. To study isotype-switched B-CLL as a potentially more differentiated variant, we performed genetic and functional immunoglobulin (Ig) gene analysis in two cases of CD5+ B-CLL in which the peripheral blood mononuclear cells (PBMC) secreted predominantly IgA (CLL-249) or IgG (CLL-412) when stimulated with pokeweed mitogen in vitro. By cDNA sequencing and by studies of CLL-heterohybridomas, CLL-249 expresses the heavy chain constant region Cα as anticipated, while CLL-412 expresses Cµ, not Cγ. In CLL-249, the expressed VH gene is 98% homologous to VH26, a germline VH3 gene that occurs frequently in the fetal repertoire, and which has been associated with anti-DNA specificity. The VL gene of CLL-249 is a X VL gene for which the germline sequence is not known. In CLL-412, the VH gene is 100% homologous to the VH1 gene of a published anti-DNA antibody (21/28), and is probably a germline gene sequence; the VL gene is 100% homologous to 15AVKI, also a germline gene. The supernatant antibody of the CLL-412 heterohybridoma is an IgM-κ, which reacts with ssDNA and cardiolipin. The CLL-249 heterohybridoma secreted IgA-λ, which bound none of the antigens tested, a finding that may be related to amino acid differences from the probable germline V genes. The demonstration of an in vivo isotype-switched variant, such as CLL-249, suggests that B-CLL may be a heterogeneous group of clonal disorders, of which less common variants may have features of more differentiated B-cell stages, such as isotype switching.