Immunoglobulin Gene Analysis in Chronic Lymphocytic Leukemia [Elektronisk resurs] Characterization of New Prognostic and Biological Subsets

• Recent studies have shown that the somatic mutation status of the immunoglobulin (Ig) V H genes can divide chronic lymphocytic leukemia (CLL) into two prognostic subsets, since cases with mutated V H genes display superior survival compared to unmutated cases. Biased V H gene usage has also been reported in CLL which may reflect antigen selection. We performed V H gene analysis in 265 CLL cases and confirmed the prognostic impact of the V H mutation status. Preferential V H gene usage was also demonstrated in both the mutated and unmutated subset. Interestingly, CLL cases rearranging one particular V H gene, V H 3-21, displayed poor outcome despite that two-thirds showed mutated V H genes. Many of the V H 3-21 cases expressed λ light chains, rearranged a V λ 2-14 gene, and had homologous complementarity determining region 3s (CDR3s), implying recognition of a common antigen epitope. We believe that the V H 3-21 subset comprises an additional CLL entity. To further explore the B-cell receptors in CLL, we analyzed the V H gene rearrangements and, specifically, the heavy chain CDR3 sequences in 346 CLL cases. We identified six new subgroups with similar HCDR3 features and restricted V L gene usage as in the V H 3-21-using group. Our data indicate a limited number of antigen recognition sites in these subgroups and give further evidence for antigen selection in the development of CLL. Different cutoffs have been suggested to distinguish mutated CLL in addition to the 2% cutoff. Using three levels of somatic mutations, i.e. <2%, 2-5% and >5%, we divided 323 CLLs into subsets with divergent survival. This division revealed a low-mutated subgroup (2-5%) with inferior outcome that would have been masked using the traditional 2% cutoff. A 1513A/C polymorphism in the P2X 7 receptor gene was reported to be more frequent in CLL, but no difference in genotype frequencies was revealed in our 170 CLL cases and 200 controls. However, CLL cases with the 1513AC genotype showed superior survival than 1513AA cases and this was in particular confined to CLL with mutated V H genes. In summary, we could define new prognostic subgroups in CLL using Ig gene rearrangement analysis. This also allowed us to gain insights in the biology and potential role of antigen involvement in the pathogenesis of CLL. 

Ämnesord

Medical and Health Sciences  (hsv)

Basic Medicine  (hsv)

Medical Genetics  (hsv)

Medicin och hälsovetenskap  (hsv)

Medicinska och farmaceutiska grundvetenskaper  (hsv)

Medicinsk genetik  (hsv)

MEDICINE  (svep)

Dermatology and venerology,clinical genetics, internal medicine  (svep)

Clinical genetics  (svep)

MEDICIN  (svep)

Dermatologi och venerologi, klinisk genetik, invärtesmedicin  (svep)

Klinisk genetik  (svep)

Genre

government publication  (marcgt)

Indexterm och SAB-rubrik

Genetics

chronic lymphocytic leukemia

immunoglobulin genes

VH3-21

CDR3

P2X7

Genetik