V(H)3-21 gene usage in chronic lymphocytic leukemia--characterization of a new subgroup with distinct molecular features and poor survival |
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Authors: | Tobin Gerard Söderberg Ola Thunberg Ulf Rosenquist Richard |
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Institution: |
a Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
b Department of Oncology, Radiology and Clinical Immunology, Uppsala University, Uppsala, Sweden |
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Abstract: | During recent years it has become evident that lymphoproliferative diseases of B-cell origin display preferential immunoglobulin (Ig) variable heavy chain (VH) gene usage. For instance, the VH1-69 and VH4-34 genes were early found to be overexpressed in B-cell chronic lymphocytic leukemia (CLL) and other B-cell lymphomas. The implications of biased VH gene usage have been speculated to be a result of stimulation of unknown antigens, which gives increased proliferation of B-cells with certain VH gene configuration and consequently higher probability to undergo transformation. Thus, VH gene usage may play a role in development of leukemias and lymphomas. Recently, we could confirm the over usage of the VH1-69 and VH4-34 genes in CLL, but a novel finding was that the VH3-21 gene was preferentially utilized in CLL patients with mutated VH genes. These VH3-21+ Ig rearrangements showed molecular peculiarities such as shorter lengths of the third complementarity determining region (CDR) and had similar amino acid composition of their CDR3s, implicating recognition of the same antigen in individual tumors. Most of the VH3-21+ patients also showed a predominance of λ chain expression and biased usage of 1 specific Vλ gene, V2-14. Furthermore, overall survival appeared to correlate with VH3-21 usage and, regardless of VH gene mutation status, VH3-21+ patients had a poor outcome. All in all, it appears that VH3-21 gene usage define a new entity of CLL. The remaining question now to be clarified is if antigen(s) actually are involved in the pathogenesis of VH3-21+ CLL. |
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Keywords: | Chronic lymphocytic leukemia Immunoglobulin genes Somatic hypermutation VH3-21 gene usage Complementarity determining region |
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