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JMD 2007, Vol. 9, No. 1
Copyright © 2007 American Society for Investigative Pathology & Association for Molecular Pathology

Telomeric IGH Losses Detectable by Fluorescence in Situ Hybridization in Chronic Lymphocytic Leukemia Reflect Somatic V_H Recombination Events

Iwona Wlodarska^*, Christine Matthews, Ellen Veyt^*, Helena Pospisilova^*, Mark A. Catherwood, Tim S. Poulsen, Vera Vanhentenrijk^¶, Rachel Ibbotson^||, Peter Vandenberghe^*, T.C.M. "Curly" Morris and H. Denis Alexander

From the Center for Human Genetics * and the Department of Pathology, ^¶ Catholic University Leuven, Leuven, Belgium; the Department of Haematology, Belfast City Hospital, Belfast, Northern Ireland; the School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland; DakoCytomation Denmark A/S, Glostrup, Denmark; and the Department of Pathology, ^|| Royal Bournemouth Hospital, Bournemouth, United Kingdom

Routine interphase fluorescence in situ hybridization (FISH) analysis of chronic lymphocytic leukemia (CLL) with LSI IGH/CCND1 assay, applied to differentiate CLL from leukemic mantle cell lymphoma, identified a subset of cases (42/174) with translocation-like IGH signal pattern. To unravel the underlying 14q32/IGH aberrations, 14 of these cases were subjected to cytogenetic, detailed FISH, and V_H mutation analyses. FISH identified cryptic losses of various portions of the IGHV region in all 14 cases. Fine mapping of these V_H deletions revealed a strict correlation between their distal border and localization of the used V_H gene, suggesting that they are not oncogenic but reflect physiological events accompanying somatic V-D-J assembly. This hypothesis was further supported by FISH analysis of 20 CLL and hairy cell leukemia cases with the known V_H usage showing a constant loss of sequences proximal to the used gene, identification of V_H deletions in normal B cells, and their exclusive demonstration in B cell malignancies, but not of T cell and myeloid linage. Given that these cryptic physiological V_H losses in B cells may seriously complicate analysis of B cell leukemia/lymphoma and lead to false conclusions, FISH users should take them into consideration when interpreting IGH aberrations in these malignancies.

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