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, Sonia Jain, George F Widhopf II, Laura Z. Rassenti, Michael J. Keating, William G. Wierda, John G. Gribben, Jennifer R. Brown, Kanti R. Rai, John C. Byrd, Neil Elliot Kay, Andrew W. Greaves, Thomas J. Kipps

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Abstract

We examined the chronic lymphocytic leukemia (CLL) cells of 2457 patients evaluated by the CLL Research Consortium (CRC) and found that 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, was 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 with that of cases without a defined HCDR3 motif, as did cases that used mutated IGHV3-21 (n = 27) versus unmutated IGHV3-21 (n = 30). Of 7 examined cases that used Ig encoded by IGHV3-21/IGLV3-21, we found that 5 had a functionally rearranged IGKV allele that apparently had incurred antigendriven somatic mutations and subsequent rearrangement with KDE. This study reveals that CLL cells expressing IGHV3-21IIGLV3-21 most likely were derived from B cells that had experienced somatic mutation and germinal-center maturation in an apparent antigen-driven immune response before undergoing Ig-receptor edit ing and after germinal-center leukemogenic selection.

Original languageEnglish (US)
Pages (from-to)5101-5108
Number of pages8
JournalBlood
Volume111
Issue number10
DOIs
StatePublished - May 15 2008

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Immunoglobulin Heavy Chains
Germinal Center
B-Cell Chronic Lymphocytic Leukemia
Immunoglobulins
Antigens
Cells
Complementarity Determining Regions
Immunoglobulin Light Chains
Mutation
Histocompatibility Antigens Class II
Amino Acid Sequence
B-Lymphocytes
Genes
Alleles
Amino Acids
Research
Therapeutics

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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Use of IGHV3-21 in chronic lymphocytic leukemia is associated with high-risk disease and reflects antigen-driven, post-germinal center leukemogenic selection. / Ghia, Emanuela M.; Jain, Sonia; II, George F Widhopf; Rassenti, Laura Z.; Keating, Michael J.; Wierda, William G.; Gribben, John G.; Brown, Jennifer R.; Rai, Kanti R.; Byrd, John C.; Kay, Neil Elliot; Greaves, Andrew W.; Kipps, Thomas J.

In: Blood, Vol. 111, No. 10, 15.05.2008, p. 5101-5108.

Research output: Contribution to journalArticle

Ghia, EM, Jain, S, II, GFW, Rassenti, LZ, Keating, MJ, Wierda, WG, Gribben, JG, Brown, JR, Rai, KR, Byrd, JC, Kay, NE, Greaves, AW & Kipps, TJ 2008, 'Use of IGHV3-21 in chronic lymphocytic leukemia is associated with high-risk disease and reflects antigen-driven, post-germinal center leukemogenic selection', Blood, vol. 111, no. 10, pp. 5101-5108. https://doi.org/10.1182/blood-2007-12-130229
Ghia, Emanuela M. ; Jain, Sonia ; II, George F Widhopf ; Rassenti, Laura Z. ; Keating, Michael J. ; Wierda, William G. ; Gribben, John G. ; Brown, Jennifer R. ; Rai, Kanti R. ; Byrd, John C. ; Kay, Neil Elliot ; Greaves, Andrew W. ; Kipps, Thomas J. / Use of IGHV3-21 in chronic lymphocytic leukemia is associated with high-risk disease and reflects antigen-driven, post-germinal center leukemogenic selection. In: Blood. 2008 ; Vol. 111, No. 10. pp. 5101-5108.
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abstract = "We examined the chronic lymphocytic leukemia (CLL) cells of 2457 patients evaluated by the CLL Research Consortium (CRC) and found that 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, was 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 with that of cases without a defined HCDR3 motif, as did cases that used mutated IGHV3-21 (n = 27) versus unmutated IGHV3-21 (n = 30). Of 7 examined cases that used Ig encoded by IGHV3-21/IGLV3-21, we found that 5 had a functionally rearranged IGKV allele that apparently had incurred antigendriven somatic mutations and subsequent rearrangement with KDE. This study reveals that CLL cells expressing IGHV3-21IIGLV3-21 most likely were derived from B cells that had experienced somatic mutation and germinal-center maturation in an apparent antigen-driven immune response before undergoing Ig-receptor edit ing and after germinal-center leukemogenic selection.",
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AU - Ghia, Emanuela M.

AU - Jain, Sonia

AU - II, George F Widhopf

AU - Rassenti, Laura Z.

AU - Keating, Michael J.

AU - Wierda, William G.

AU - Gribben, John G.

AU - Brown, Jennifer R.

AU - Rai, Kanti R.

AU - Byrd, John C.

AU - Kay, Neil Elliot

AU - Greaves, Andrew W.

AU - Kipps, Thomas J.

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N2 - We examined the chronic lymphocytic leukemia (CLL) cells of 2457 patients evaluated by the CLL Research Consortium (CRC) and found that 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, was 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 with that of cases without a defined HCDR3 motif, as did cases that used mutated IGHV3-21 (n = 27) versus unmutated IGHV3-21 (n = 30). Of 7 examined cases that used Ig encoded by IGHV3-21/IGLV3-21, we found that 5 had a functionally rearranged IGKV allele that apparently had incurred antigendriven somatic mutations and subsequent rearrangement with KDE. This study reveals that CLL cells expressing IGHV3-21IIGLV3-21 most likely were derived from B cells that had experienced somatic mutation and germinal-center maturation in an apparent antigen-driven immune response before undergoing Ig-receptor edit ing and after germinal-center leukemogenic selection.

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