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Blood, 1 May 2004, Vol. 103, No. 9, pp. 3490-3495. Prepublished online as a Blood First Edition Paper on December 24, 2003; DOI 10.1182/blood-2003-10-3407. This Article Full Text (PDF) All Versions of this Article: 2003-10-3407v1 103/9/3490    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Messmer, B. T Articles by Chiorazzi, N. Search for Related Content PubMed PubMed Citation Articles by Messmer, B. T Articles by Chiorazzi, N. Social Bookmarking                   What's this? Submitted October 3, 2003 Accepted November 28, 2003 The Pattern and distribution of immunoglobulin VH gene mutations in chronic lymphocytic leukemia B cells are consistent with the canonical somatic hypermutation process Bradley T Messmer*, Emilia Albesiano, Davorka Messmer, and Nicholas Chiorazzi Department of Experimental Immunology, North Shore - LIJ Research Institute, Manhasset, NY, USA Departments of Medicine, North Shore University Hospital and NYU School of Medicine, Manhasset, NY, USA * Corresponding author; email: bmessmer{at}nshs.edu. The over-expanded clone in most B-CLL patients expresses an Ig H chain variable (VH) region gene with some level of mutation. While it is presumed that these mutations were introduced in the progenitor cell of the leukemic clone by the canonical somatic hypermutation (SHM) process, direct evidence of such is lacking. Nucleotide sequences of the Ig VH genes from 172 B-CLL patients were analyzed. Previously described VH gene usage biases were noted. As with canonical SHM, mutations found in B-CLL were more frequent in RGYW hotspots (mutations in an RGYW motif = 44.1%; germline frequency of RGYW motifs = 25.6%) and favored transitions over transversions (transition/transversion = 1.29). Significantly, transition preference was also noted when only mutations in the wobble position of degenerate codons were considered. Wobble positions are inherently unselected since regardless of change an identical amino acid is encoded; therefore they represent a window into the nucleotide bias of the mutational mechanism. B-CLL VH mutations concentrated in CDR1 and CDR2, which exhibited higher replacement to silent ratios (CDR R:S: 4.60, FR R:S: 1.72). These results are consistent with the notion that VH mutations in B-CLL cells result from canonical SHM and select for altered, structurally sound antigen receptors. 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