Use of IGHV3-21 in chronic lymphocytic leukemia is associated with high-risk disease and reflects antigen-driven, post-germinal-center leukemogenic selection

March 17, 2008

Use of IGHV3-21 in chronic lymphocytic leukemia is associated with high-risk

disease and reflects antigen-driven, post-germinal-center leukemogenic

selection.

Emanuela M Ghia, Jain, F Widhopf, Z Rassenti, J

Keating, G Wierda, G Gribben, R Brown, Kanti R Rai, C

Byrd, Neil E Kay, W Greaves, and J Kipps

Blood, March 7, 2008; .

s Cancer Center, Division of Hematology/Oncology, Department of Medicine,

University of California, San Diego, La Jolla, CA, United States.

We examined the chronic lymphocytic leukemia (CLL) cells of 2,457 patients

evaluated by the CLL Research Consortium and found 63 (2.6%) expressed

immunoglobulin (Ig) encoded by the Ig heavy-chain-variable-region gene (IGHV),

IGHV3-21. We identified the amino-acid sequence DANGMDV (motif-1) or

DPSFYSSSWTLFDY (motif-2) in the Ig heavy-chain (IgH) third

complementarity-determining region (HCDR3) of IgH respectively used by 25 or 3

cases. The IgH with HCDR3 motif-1 or motif-2 respectively were paired with Ig

light chains (IgL) encoded by IGLV3-21 or IGKV3-20, suggesting that these Ig had

been selected for binding to conventional antigen(s). Cases that had HCDR3

motif-1 had a median time from diagnosis to initial therapy comparable to that

of cases without a defined HCDR3 motif, as did cases that used mutated IGHV3-21

(n=30) versus unmutated IGHV3-21 (n=33). Of seven examined cases that used Ig

encoded by IGHV3-21/IGLV3-21, we found that five had a functionally-rearranged

IGKV allele that apparently had incurred antigen-driven somatic mutations and

subsequent rearrangement with KDE. This study reveals that CLL cells expressing

IGHV3-21/IGLV3-21 most likely were derived from B cells that had experienced

somatic mutation and germinal-center maturation in an apparent antigen-driven

immune response prior to undergoing Ig-receptor editing and post germinal-center

leukemogenic selection.

PMID: 18326815

Recommended Posts