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      ZAP-70: un nuevo factor pronóstico en la leucemia linfoide crónica Translated title: ZAP-70: a new prognostic factor in chronic lymphocytic leukemia

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          Abstract

          En la leucemia linfoide crónica de tipo B (LLC-B) se han planteado diferentes factores pronósticos para predecir la evolución de la enfermedad. En fecha reciente se ha añadido un nuevo factor pronóstico determinado por la expresión de una proteina de 70 Kda que se asocia con la cadena Z de receptor de las células T, y que se representa por la abreviatura ZAP-70. Esta proteína no se expresa en los linfocitos B normales, pero sí en los de un subgrupo de LLC-B que no tiene mutaciones en los genes de la región variable de la cadena pesada de las inmunoglobulinas (IgVH). Estudios recientes sugieren que la expresión de esta proteína en los linfocitos leucémicos podría contribuir a la evolución más agresiva que pueden tener las LLC-B sin mutaciones en los genes IgVH. Se ha señalado que la determinación de la ZAP-70 puede proporcionar un indicador pronóstico más simple que la caracterización del estado mutacional de los genes IgVH

          Translated abstract

          In B-cell chronic lymphocytic leukemia (B-CLL), different prognostic factors have been presented to predict the course of the disease. Recently, there has been added a new prognostic factor determined by the expression of 70kDa protein that is associated with T-cell receptor zeta chain and known as ZAP-70. This protein does not express in normal B lymphocytes but it does in those of a B-CLL subgroup that do not have IgVH heavy chain variable-region gene mutations. Recent studies indicate that the expression of this protein in leukemic lymphocytes could contribute to a more aggressive course of B-cell chronic lymphocytic leukemia without IgVH gene mutations. Likewise, it has been pointed out that the determination of ZAP-70 can provide a simpler prognostic factor than the present characterization of the IgVH gene mutational state

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          Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia.

          Cellular immunophenotypic studies were performed on a cohort of randomly selected IgM(+) B-chronic lymphocytic leukemia (B-CLL) cases for which Ig V(H) and V(L) gene sequences were available. The cases were categorized based on V gene mutation status and CD38 expression and analyzed for treatment history and survival. The B-CLL cases could be divided into 2 groups. Those patients with unmutated V genes displayed higher percentages of CD38(+) B-CLL cells (>/=30%) than those with mutated V genes that had lower percentages of CD38(+) cells ( /=30% CD38(+) groups responded poorly to continuous multiregimen chemotherapy (including fludarabine) and had shorter survival. In contrast, the mutated and the /=30% CD38(+) groups, a marked male predominance was found. Thus, Ig V gene mutation status and the percentages of CD38(+) B-CLL cells appear to be accurate predictors of clinical outcome in B-CLL patients. These parameters, especially CD38 expression that can be analyzed conveniently in most clinical laboratories, should be valuable adjuncts to the present staging systems for predicting the clinical course in individual B-CLL cases. Future evaluations of new therapeutic strategies and drugs should take into account the different natural histories of patients categorized in these manners.
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            Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia.

            Despite having several characteristics of naïve B cells, chronic lymphocytic leukemia (CLL) cells have been shown in some cases to have somatically mutated Ig variable region genes, indicating that the cell of origin has passed through the germinal center. A previous study of patients with CLL found an association between lack of somatic mutation and trisomy 12 and, therefore, possibly with a less favorable prognosis. We have sequenced the Ig V(H) genes of the tumor cells of 84 patients with CLL and correlated our findings with clinical features. A total of 38 cases (45.2%) showed >/= 98% sequence homology with the nearest germline V(H) gene; 46 cases (54.8%) showed >2% somatic mutation. Unmutated V(H) genes were significantly associated with V1-69 and D3-3 usage, with atypical morphology; isolated trisomy 12, advanced stage and progressive disease. Survival was significantly worse for patients with unmutated V(H) genes irrespective of stage. Median survival for stage A patients with unmutated V(H) genes was 95 months compared with 293 months for patients whose tumors had mutated V(H) genes (P =.0008). The simplest explanation is that CLL comprises 2 different diseases with different clinical courses. One, arising from a memory B cell, has a benign course, the other, arising from a naïve B cell, is more malignant.
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              Relation of Gene Expression Phenotype to Immunoglobulin Mutation Genotype in B Cell Chronic Lymphocytic Leukemia

              The most common human leukemia is B cell chronic lymphocytic leukemia (CLL), a malignancy of mature B cells with a characteristic clinical presentation but a variable clinical course. The rearranged immunoglobulin (Ig) genes of CLL cells may be either germ-line in sequence or somatically mutated. Lack of Ig mutations defined a distinctly worse prognostic group of CLL patients raising the possibility that CLL comprises two distinct diseases. Using genomic-scale gene expression profiling, we show that CLL is characterized by a common gene expression “signature,” irrespective of Ig mutational status, suggesting that CLL cases share a common mechanism of transformation and/or cell of origin. Nonetheless, the expression of hundreds of other genes correlated with the Ig mutational status, including many genes that are modulated in expression during mitogenic B cell receptor signaling. These genes were used to build a CLL subtype predictor that may help in the clinical classification of patients with this disease.
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                Author and article information

                Journal
                hih
                Revista Cubana de Hematología, Inmunología y Hemoterapia
                Rev Cubana Hematol Inmunol Hemoter
                Centro Nacional de Información de Ciencias Médicas; Editorial Ciencias Médicas (La Habana, , Cuba )
                0864-0289
                1561-2996
                December 2004
                : 20
                : 3
                Affiliations
                [01] Ciudad de La Habana orgnameInstituto de Hematología e Inmunología Cuba ihidir@ 123456hemato.sld.cu
                Article
                S0864-02892004000300007 S0864-0289(04)02000307
                9c4be183-6131-4e45-9488-3806ec14e8ff

                This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

                History
                : 02 November 2004
                : 18 November 2004
                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 20, Pages: 0
                Product

                SciELO Cuba

                Categories
                MINI-REVISIONES

                genes IgV-H,ZAP-70,CD38,factores,LLC-B,IgVH genes,prognostic factors,B-CLL

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