IGHV gene rearrangements as outcome predictors for CLL patients: experience of Ukrainian group.
ABSTRACT Important characteristics of chronic lymphocytic leukaemia (CLL) cells are biased immunoglobulin variable heavy chain (IGHV) gene repertoire and expression of stereotyped B-cell receptors (BCRs); however, their prognostic value (in contrast to the impact of IGHV gene mutational status) is less clear. To evaluate the impact of separate IGHV gene usage and expression of stereotyped BCRs in CLL prognosis. Clinical data and IGHV gene configuration were analysed in 319 consecutive patients with CLL. We found that the majority of clinical parameters of patients were defined by IGHV mutational status. Our data also provided new evidence supporting the prognostic relevance of separate IGHV genes or stereotyped BCR in CLL, namely: (a) a restricted non-mutated (UM) IGHV gene repertoire in CLL patients with autoimmune haemolytic anaemia (AIHA) (more frequent expression of UM IGHV1-69, IGHV3-11 and IGHV4-59 genes, P = 0.001), a shorter period of AIHA development for expressors of these genes (P = 0.001) and a tendency towards expression of a stereotypic HCDR3 (P = 0.029), (b) a high incidence of second solid tumour development in IGHV3-21-expressing patients (P = 0.005) and (c) differences in overall survival (OS) of UM CLL patients depending on the BCR structure. Further research of specific IGHV gene usage and subsets of stereotyped BCRs in CLL may be helpful in more precise prediction of CLL prognosis in individual patients.
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ABSTRACT: The mutational status of the immunoglobulin variable region heavy chain genes (IGHV) is an important prognostic marker in chronic lymphocytic leukemia (CLL). The data accumulated in the literature has largely been derived from studies conducted on Caucasian Western populations. Little is known about Asian CLL patients. In this study the IGHV genes usage and somatic hypermutation status have been investigated in 87 Iranian CLL patients. Based on a cut-off of 98% nucleotide sequence homology, 64.4% and 35.6% of the patients expressed mutated and unmutated IGHV genes, respectively, with most non-progressive patients being in the mutated group (35/44 vs 19/40; P = 0.009). Progression-free survival (PFS) and time to first treatment (TTFT) were significantly higher in our mutated and non-progressive patients compared to unmutated and progressive subtypes, respectively. The most frequently used IGHV gene was IGHV3-7 (12.6%) followed by IGHV3-30 (11.4%), IGHV3-48 (9.2%), IGHV4-39 (6.9%), and IGHV1-8 (6.9%) genes, which taken together comprised nearly half of the IGHV genes expressed in the Iranian CLL patients. Of the IGHV genes, IGHV3-7 was significantly over-represented in non-progressive compared to progressive CLL patients (P = 0.036), whereas IGHV1-69 and IGHV1-2 were expressed at a higher frequency in unmutated compared to mutated CLL patients (P < 0.03). Comparison of IGHV gene usage in our patients with that of Western CLL patients revealed significant differences in expression of IGHV1-69, IGHV3-7, IGHV3-21, and IGHV4-34 genes. Analysis of the IGHV third complementary determining region (HCDR3) sequences revealed a high frequency use of certain HCDR3 motifs, such as YYYGMDV, in our samples. These findings imply contribution of antigen selection and regional (ethnic/geographic) parameters in the leukomogenesis of CLL.Cancer Science 09/2009; 100(12):2346-53. · 3.48 Impact Factor
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ABSTRACT: B-cell chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease with many patients surviving for decades with minimal or no treatment, whereas others succumb rapidly to their disease despite therapy. In recent years, new molecular prognostic factors have emerged in CLL that have significantly improved the subgrouping of the disease. One of the most important molecular predictors, the immunoglobulin V(H) gene mutation status, divides CLL into two prognostic groups, depending on the presence or absence of somatic hypermutation, where unmutated V(H) genes are associated with considerably worse prognosis than mutated V(H) genes. An exception to this appears to be CLL patients utilizing the V(H)3-21 gene as they have poor outcome irrespective of mutation status. Surrogate markers for the VH gene mutation status have been suggested, such as CD38 and ZAP-70 expression. However, the CD38 level was later shown to display poor correlation to the mutation status, although it may still serve as an independent prognostic factor. More promising is the expression levels of ZAP-70, which appears to be both a strong surrogate marker for V(H) gene mutation status, although discrepancies have been reported, as well as an independent prognostic marker. Immunoglobulin gene analysis has also indicated the possibility of antigen selection in CLL considering the significant bias in V(H) gene usage. Intriguingly, the V(H)3-21+ group and several other CLL subsets using certain V(H) genes was recently reported to display strikingly restricted immunoglobulin gene features, in both their heavy and light chain gene rearrangements, thus further high-lighting the possible role of antigen involvement in CLL development.Medical Oncology 02/2005; 22(3):217-28. · 2.15 Impact Factor
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ABSTRACT: The mechanisms underlying the frequent association between chronic lymphocytic leukemia (CLL) and autoimmune hemolytic anemia are currently unclear. The erythrocyte protein band 3 (B3) is one of the most frequently targeted Ags in autoimmune hemolytic anemia. In this study, we show that CLL cells specifically recognize B3 through a still unidentified receptor. B3 interaction with CLL cells involves the recognition of its N-terminal domain and leads to its internalization. Interestingly, when binding of erythrocyte-derived vesicles as found physiologically in blood was assessed, we observed that CLL cells could only interact with inside-out vesicles, being this interaction strongly dependent on the recognition of the N-terminal portion of B3. We then examined T cell responses to B3 using circulating CLL cells as APCs. Resting B3-pulsed CLL cells were unable to induce T cell proliferation. However, when deficient costimulation was overcome by CD40 engagement, B3-pulsed CLL cells were capable of activating CD4(+) T cells in a HLA-DR-dependent fashion. Therefore, our work shows that CLL cells can specifically bind, capture, and present B3 to T cells when in an activated state, an ability that could allow the neoplastic clone to trigger the autoaggressive process against erythrocytes.The Journal of Immunology 10/2008; 181(5):3674-83. · 5.52 Impact Factor