The IGHV1-69/IGHJ3 recombinations of unmutated CLL are distinct from those of normal B cells

Blood. 2012 Mar 1;119(9):2106-9. doi: 10.1182/blood-2011-08-375501. Epub 2012 Jan 10.

Abstract

IGHV1-69/51p1 is expressed by ∼ 30% of unmutated chronic lymphocytic leukemia (U-CLL) and combines with selected IGHD and IGHJ genes generating stereotypes if HCDR3 amino acid homology is > 60%. We had previously revealed stereotypic IGHV1-69/IGHJ6 rearrangements in normal naive B cells, thereby identifying potential counterparts of U-CLL. A different stereotypic IGHV1-69/IGHD3-16(RF2)/IGHJ3 rearrangement carrying the CAR(GGx)YD motif in the N1-region, recurrent in 6% IGHV1-69+ve CLL, is exceptionally sequence restricted, strongly suggestive of shared antigen recognition. We have now analyzed IGHV1-69/IGHJ3 rearrangements in circulating B cells of healthy individuals using several PCR-based approaches with IGHV1-69/IGHJ3 CLL sequences for reference. Stereotypes were found, but all were distinct from CLL. Remarkably, even a highly sensitive semi-nested PCR, specific for the CLL-expressed IGHV1-69/IGHD3-16(RF2)/IGHJ3 stereotype, failed to identify the CAR(GGx)YD sequence, although similar motifs were found. These highly specific B cells are not apparent in the accessible normal repertoire and may expand in response to rarely expressed antigens important in the pathogenesis of CLL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • B-Lymphocytes / metabolism*
  • Gene Rearrangement, B-Lymphocyte, Heavy Chain / genetics*
  • Humans
  • Immunoglobulin Heavy Chains / genetics*
  • Immunoglobulin Variable Region / genetics*
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
  • Sequence Alignment
  • V(D)J Recombination / genetics*

Substances

  • Immunoglobulin Heavy Chains
  • Immunoglobulin Variable Region