Journal
BLOOD
Volume 114, Issue 20, Pages 4460-4468Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2009-05-221309
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Funding
- Swedish Cancer Society
- Swedish Medical Research Council
- Medical Faculty of Uppsala University
- Uppsala University Hospital
- Lion's Cancer Research Foundation, Uppsala, Sweden
- BioSapiens Network of Excellence [LSHG-CT-2003-503265]
- General Secretariat for Research and Technology of Greece
- Propondis Foundation, Athens, Greece
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Several studies indicate that the development of chronic lymphocytic leukemia (CLL) may be influenced by antigen recognition through the clonotypic B-cell receptors (BCRs). However, it is still unclear whether antigen involvement is restricted to the malignant transformation phase or whether the putative antigen(s) may continuously trigger the CLL clone and affect not only the progenitor cell but also the leukemic cells themselves. To address this issue, we conducted a large-scale subcloning study of rearranged immunoglobulin heavy variable (IGHV) genes of diverse mutational status from 71 CLL cases (total, 1496 subcloned sequences), belonging to both the common IgM/IgD variant and the rare IgG-positive variant. Although most cases showed no or low levels of intraclonal diversification (ID), we report intense ID in the IGHV genes of selected cases, especially a subgroup of 13 IgG-switched cases expressing stereotyped, mutated IGHV4-34 rearrangements (subset 4). We demonstrate that the ID evident in subset 4 cases cannot be attributed to IGHV4-34 usage, IGHV genemutated status, class-switch recombination, or BCR stereotypy in general; rather, it represents a unique phenomenon strongly correlated with the distinctive BCR of subset 4. In such cases, the observed ID patterns may imply a stereotyped response to an active, ongoing interaction with antigen(s). (Blood. 2009;114:4460-4468)
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