Mutational Status of IgVH Genes Consistent with Antigen-Driven Selection but Not Percent of Mutations Has Prognostic Impact in B-Cell Chronic Lymphocytic Leukemia

Degan, Massimo; Rupolo, Maurizio; Bo, Michele Dal; Stefanon, Anna; Bomben, Riccardo; Zucchetto, Antonella; Canton, E.; Berretta, Massimiliano; Nanni, Paola; Steffan, Agostino; Ballerini, Pier Ferruccio; Damiani, D. Doḿınguez; Pucillo, Carlo; Attadia, Vincenza; Colombatti, Alfonso; Gattei, Valter

doi:10.3816/clm.2004.n.019

Cited by 10 publications

(16 citation statements)

References 22 publications

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“…In particular, while some of them (e.g., CD52, CD24, and CD59) displayed MFI values reaching the fourth log decade of flow cytometry plots, for other markers expression levels never exceeded the second-third log decades; this fact determined a too wide operational range (from 1 up to about 1,200) for the color scale employed in heatmaps (A. Zucchetto and V. Gattei, unpublished observation). Therefore, also in accord with previous studies (Damle et al, 1999;Del Poeta et al, 2001;Degan et al, 2004b), we decided to express data as percent of positive CD19 þ B-CLL cells. This choice, beside reducing the operational range of color scale (0-100 in all cases), facilitated clustering by decreasing the complexity of the final database (a marker expressed above the threshold corresponding to 100% of positive cells will be always considered expressed at the value of 100).…”

Section: Surface Antigen Expressionmentioning

confidence: 90%

“…Briefly, total RNA, extracted, reverse-transcribed, and checked for first-strand synthesis (Gattei et al, 1997;Degan et al, 2000), was amplified using a mixture of sense primers annealing either to the V H 1 through V H 6 leader sequences or to the 5 0 end of V H 1-V H 6 FR1 utilized in conjunction with a mixture of anti-sense primers complementary to the germ line J H regions (Fais et al, 1998;Damle et al, 1999;Hamblin et al, 1999;Gurrieri et al, 2002;Krober et al, 2002;Degan et al, 2004a). The purified amplified products were cloned into plasmids and sequenced (Degan et al, 2004a;Degan et al, 2004b). Only when the same rearrangement was identified in at least 5-10 clones, a given IgV H sequence was assigned and the number of IgV H mutations computed (Degan et al, 2004a).…”

Section: Discussionmentioning

confidence: 99%

“…Noteworthy among these markers, CD62L, CD54, and CD25 are all surface structures somewhat involved in the cross-talk between B lymphocytes with neighboring endothelial and/or T cells within the lymph node microenvironment (Lane et al, 1991;Poudrier and Owens, 1994;Gu et al, 2001;Ley, 2002;Mills and Cambier, 2003). Interestingly, B-CLL cases expressing the CD62L þ CD54 þ CD25 þ phenotype more frequently displayed high number of IgV H mutations (Damle et al, 1999;Hamblin et al, 1999;Maloum et al, 2000;Krober et al, 2002;Lin et al, 2002;Degan et al, 2004a), as well as an IgV H mutational status consistent with antigen-driven selection (Chang and Casali, 1994;Lossos et al, 2000;Degan et al, 2004b). This data is in keeping with the immunophenotypic profile of these cells, since IgV H mutations usually occur as the result of T-cell-dependent interactions during GC maturation of B cells (Dorner et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

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Signature of B‐CLL with different prognosis by Shrunken centroids of surface antigen expression profiling

Zucchetto

Sonego

Degan

et al. 2004

Journal Cellular Physiology

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With the aim of identifying the immunophenotypic profile of B-cell chronic lymphocytic leukemia (B-CLL) subsets with different prognosis, we investigated by flow cytometry the expression of 36 surface antigens in 123 cases, all with survivals. By analyzing results with unsupervised (hierarchical and K-means clustering) algorithms, three distinct immunophenotypic groups (I, II, and III) were identified, group I (51/123) with longer survivals, as compared to the group II (36/123) and III (36/123). The immunophenotypic signatures of these groups, as determined by applying the nearest Shrunken centroids method as class predictor, were characterized by the coordinated and differential expression of 12 surface markers, that is, group I: above-average expression of CD62L, CD54, CD49c, and CD25, below-average expression of CD38; group II: above-average expression of CD38, CD49d, CD29, and CD49e; and group III: below-average expression of the above markers, overexpression of CD23, CD20, SmIg, and CD79b. As opposed to groups II-III, group I B-CLLs lacked expression of ZAP-70 and activation-induced cytidine deaminase in the majority of cases, while more frequently had mutated IgV(H) genes and IgV(H) mutations consistent with antigen-driven selection. Our findings contribute to improve the immunophenotypical identification of disease subsets with different prognosis and suggest a set of surface antigens to be employed as prognosticators in routine diagnostic/prognostic procedures.

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Section: Surface Antigen Expressionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Signature of B‐CLL with different prognosis by Shrunken centroids of surface antigen expression profiling

Zucchetto

Sonego

Degan

et al. 2004

Journal Cellular Physiology

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“…[18][19][20][21][22][23][24][25] However, Chang and Casali's method does not consider the differences in the intrinsic mutability of various regions of antibody genes. Dunn-Walters and Spencer 26 have shown that CDR regions of human germline antibody genes tend intrinsically to accumulate more R mutations over S mutations.…”

Section: Abstract: Immunoglobulin Variable Regions; Somatic Mutation;mentioning

confidence: 99%

Problems in using statistical analysis of replacement and silent mutations in antibody genes for determining antigen‐driven affinity selection

Bose

Sinha

2005

Immunology

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Summary The analysis of molecular signatures of antigen‐driven affinity selection of B cells is of immense use in studies on normal and abnormal B cell development. Most of the published literature compares the expected and observed frequencies of replacement (R) and silent (S) mutations in the complementarity‐determining regions (CDRs) and the framework regions (FRs) of antibody genes to identify the signature of antigenic selection. The basic assumption of this statistical method is that antigenic selection creates a bias for R mutations in the CDRs and for S mutations in the FRs. However, it has been argued that the differences in intrinsic mutability among different regions of an antibody gene can generate a statistically significant bias even in the absence of any antigenic selection. We have modified the existing statistical method to include the effects of intrinsic mutability of different regions of an antibody gene. We used this method to analyse sequences of several B cell‐derived monoclonals against T‐dependent antigens, T‐independent antigens, clones derived from lymphoma and amyloidogenic clones. Our sequence analysis indicates that even after correcting for the intrinsic mutability of antibody genes, statistical parameters fail to reflect the role of antigen‐driven affinity selection in maturation of many clones. We suggest that, contrary to the basic assumption of such statistical methods, selection can act both for and against R mutations in the CDR as well as in the FR regions. In addition we have identified different methodological difficulties in the current uses of such statistical analysis of antibody genes.

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“…Briefly, total RNA, extracted, reverse-transcribed and checked for firststrand synthesis (Gattei et al, 1997;Degan et al, 2000), was amplified using a mixture of sense primers annealing either to the V H 1 through V H 6 leader sequences or to the 5′ end of V H 1-V H 6 FR1 utilized in conjunction with a mixture of antisense primers complementary to the germ line J H region (Fais et al, 1998;Hamblin et al, 1999;Gurrieri et al, 2002;Degan et al, 2004b). The purified amplified products were cloned into plasmids and sequenced.…”

Section: Amplification Cloning and Sequencing Of V H Dj H Transcriptsmentioning

confidence: 99%

Laminin-332 (Laminin-5) is the major motility ligand for B cell chronic lymphocytic leukemia

Spessotto

Zucchetto²,

Degan³

et al. 2007

Matrix Biology

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Mutational Status of IgVH Genes Consistent with Antigen-Driven Selection but Not Percent of Mutations Has Prognostic Impact in B-Cell Chronic Lymphocytic Leukemia

Cited by 10 publications

References 22 publications

Signature of B‐CLL with different prognosis by Shrunken centroids of surface antigen expression profiling

Signature of B‐CLL with different prognosis by Shrunken centroids of surface antigen expression profiling

Problems in using statistical analysis of replacement and silent mutations in antibody genes for determining antigen‐driven affinity selection

Laminin-332 (Laminin-5) is the major motility ligand for B cell chronic lymphocytic leukemia

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