SEPT10 Expression in Chronic Lymphocytic Leukemia. Correlation with Clinical and Biological Prognostic Factors
Affiliation(s)
Laboratorio de Genética de Neoplasias Linfoides, Instituto de Medicina Experimental, CONICET-Academia Nacional de Medicina, Buenos Aires, Argentina. División Patología Molecular, Instituto de Investigaciones Hematológicas, Academia Nacional de Medi- cina, Buenos Aires, Argentina. Servicio de Hematología, Hospital General de Agudos “Dr Teodoro álvarez”, Buenos Aires, Ar- gentina..
Laboratorio de Genética de Neoplasias Linfoides, Instituto de Medicina Experimental, CONICET-Academia Nacional de Medicina, Buenos Aires, Argentina. División Patología Molecular, Instituto de Investigaciones Hematológicas, Academia Nacional de Medi- cina, Buenos Aires, Argentina. Servicio de Hematología, Hospital General de Agudos “Dr Teodoro álvarez”, Buenos Aires, Ar- gentina..
ABSTRACT
Chronic lymphocytic leukemia (CLL) is characterized by a highly variable clinical course. Microarray studies allowed highlight genes differentially expressed in this pathology. In this study, we have evaluated the prognostic significance of SEPT10 expression in CLL patients. Results were correlated with immunoglobulin heavy-chain variable (IGHV) genes mutational status, genomic rearrangements and clinical parameters. SEPT10 mRNA levels were determined by quantitative real-time PCR in 70 newly diagnosed CLL patients consecutively referred to our Institution. A wide heterogeneity for SEPT10 expression was found. Gene upregulation was observed in 18.5% of cases. The univariate analysis showed a positive association between gen expression and platelet count (p < 0.0001) and a negative correlation with hemoglobin levels (p = 0.0094). Although no significant differences were observed, mean treatment free survival was shorter in patients with high expression (31 months) with respect to those with low mRNA levels (72 months). Cases with abnormal karyotypes had increased expression compared to those with normal karyotypes and no association between gene expression and FISH (fluorescence in situ hybridization) risk groups and IGHV mutational status was found. Cases using IGHV3-23 gene rearrangement had low SEPT10 expression. Our results showed an association between SEPT10 expression and features of adverse outcome but without independent prognostic value. The study of SEPT10 expression may be important for a better understanding of disease heterogeneity, adding further information to those provided by established prognostic factors.
Chronic lymphocytic leukemia (CLL) is characterized by a highly variable clinical course. Microarray studies allowed highlight genes differentially expressed in this pathology. In this study, we have evaluated the prognostic significance of SEPT10 expression in CLL patients. Results were correlated with immunoglobulin heavy-chain variable (IGHV) genes mutational status, genomic rearrangements and clinical parameters. SEPT10 mRNA levels were determined by quantitative real-time PCR in 70 newly diagnosed CLL patients consecutively referred to our Institution. A wide heterogeneity for SEPT10 expression was found. Gene upregulation was observed in 18.5% of cases. The univariate analysis showed a positive association between gen expression and platelet count (p < 0.0001) and a negative correlation with hemoglobin levels (p = 0.0094). Although no significant differences were observed, mean treatment free survival was shorter in patients with high expression (31 months) with respect to those with low mRNA levels (72 months). Cases with abnormal karyotypes had increased expression compared to those with normal karyotypes and no association between gene expression and FISH (fluorescence in situ hybridization) risk groups and IGHV mutational status was found. Cases using IGHV3-23 gene rearrangement had low SEPT10 expression. Our results showed an association between SEPT10 expression and features of adverse outcome but without independent prognostic value. The study of SEPT10 expression may be important for a better understanding of disease heterogeneity, adding further information to those provided by established prognostic factors.
KEYWORDS
Chronic Lymphocytic Leukemia; SEPT10 Expression; FISH; Cytogenetics; IGHV Mutational Status
Chronic Lymphocytic Leukemia; SEPT10 Expression; FISH; Cytogenetics; IGHV Mutational Status
Cite this paper
A. Travella, J. Panero, C. Stanganelli, R. Bezares and I. Slavutsky, "SEPT10 Expression in Chronic Lymphocytic Leukemia. Correlation with Clinical and Biological Prognostic Factors," Open Journal of Blood Diseases, Vol. 3 No. 3, 2013, pp. 11-16. doi: 10.4236/ojbd.2013.33A003.
A. Travella, J. Panero, C. Stanganelli, R. Bezares and I. Slavutsky, "SEPT10 Expression in Chronic Lymphocytic Leukemia. Correlation with Clinical and Biological Prognostic Factors," Open Journal of Blood Diseases, Vol. 3 No. 3, 2013, pp. 11-16. doi: 10.4236/ojbd.2013.33A003.
References
[1] N. Chiorazzi, K. R. Rai and M. Ferrarini, “Chronic Lymphocytic Leukemia,” New England Journal of Medicine, Vol. 352, No. 8, 2005, pp. 804-815. http://dx.doi.org/10.1056/NEJMra041720 [2] H. Dohner, S. Stilgenbauer, A. Benner, E. Leupolt, A. Krober, L. Bullinger, et al., “Genomic Aberrations and Survival in Chronic Lymphocytic Leukemia,” New England Journal of Medicine, Vol. 343, No. 26, 2000, pp. 1910-1916. http://dx.doi.org/10.1056/NEJM200012283432602 [3] R. N. Damle, T. Wasil, F. Fais, F. Ghiotto, A. Valetto, S. L. Allen, et al., “Ig V Gene Mutation Status and CD38 Expression as Novel Prognostic Indicators in Chronic Lymphocytic Leukaemia,” Blood, Vol. 94, No. 6, 1999, pp. 1840-1847. [4] T. J. Hamblin, Z. Davis, A. Gardiner, D. G. Oscier and F. K. Stevenson, “Unmutated Ig VH Genes Are Associated with a More Aggressive Form of Chronic Lymphocytic Leukaemia,” Blood, Vol. 94, No. 6, 1999, pp. 1848-1854. [5] P. A. Hall, K. Jung, K. J. Hillan and S. E. Russell, “Expression Profiling the Human Septin Gene Family,” Journal of Pathology, Vol. 206, No. 3, 2005, pp. 269-278. http://dx.doi.org/10.1002/path.1789 [6] M. Liu, S. Shen, F. Chen, W. Yu and L. Yu, “Linking the Septin Expression with Carcinogenesis,” Molecular Biology Reports, Vol. 37, No. 7, 2010, pp. 3601-3608. http://dx.doi.org/10.1007/s11033-010-0009-2 [7] B. E. Kremer, T. Haysted and I. G. Macara, “Mammalian Septins Regulate Microtubule Stability through Interaction with the Microtubule-Binding Protein MAP4”, Molecular Biology of the Cell, Vol. 16, No. 10, 2005, pp. 4648-4659. http://dx.doi.org/10.1091/mbc.E05-03-0267 [8] M. Xu, M. Takanashi, K. Oikawa, H. Nishi, K. Isaka, T. Yoshimoto, et al., “Identification of a Novel Role of Septin 10 in Paclitaxel-Resistance in Cancers through a Functional Genomic Screen,” Cancer Science, Vol. 103, No. 4, 2012, pp. 821-827. http://dx.doi.org/10.1111/j.1349-7006.2012.02221.x [9] M. Bilban, D. Heintel, T. Scharl, T. Woelfel, M. M. Auer, E. Porpaczy, et al., “Deregulated Expression of Fat and Muscle Genes in B-Cell Chronic Lymphocytic Leukemia with High Lipoprotein Lipase Expression,” Leukemia, Vol. 20, No. 6, 2006, pp. 1080-1088. http://dx.doi.org/10.1038/sj.leu.2404220 [10] M. B. Van’t Veer, A. M. Brooijmans, A. W. Langerak, B. Verhaaf, C. S. Goudswaard, W. J. Graveland, et al., “The Predictive Value of Lipoprotein Lipase for Survival in Chronic Lymphocytic Leukemia,” Haematologica, Vol. 91, No. 1, 2006, pp. 56-63. [11] M. Hallek, B. D. Cheson, D. Catovsky, F. Caligaris-Cappio, G. Dighiero, H. Dohner, et al., “Guidelines for the Diagnosis and Treatment of Chronic Lymphocytic Leukemia: A Report from the International Workshop on Chronic Lymphocytic Leukemia Updating the National Cancer Institute-Working Group 1996 Guidelines,” Blood, Vol. 111, No. 12, 2008, pp. 5446-5456. [12] K. R. Rai, A. Sawitsky, E. P. Cronkite, A. D. Chanana, R. N. Levy and B. S. Pasternack, “Clinical Staging of Chronic Lymphocytic Leukemia,” Blood, Vol. 46, No. 2, 1975, pp. 219-234. [13] L. H. Hu, F. H. Chen, Y. R. Li and L. Wang, “Real-Time Determination of Human Telomerase Reverse Transcriptase mRNA in Gastric Cancer,” World Journal of Gastroenterology, Vol. 10, No. 23, 2004, pp. 3514-3517. [14] C. Stanganelli, A. Travella, R. Bezares and I. Slavutsky, “Immunoglobulin Gene Rearrangements and Mutational Status in Argentinean Patients with Chronic Lymphocytic Leukemia,” Clinical Lymphoma Myeloma and Leukemia, Vol. 13, No. 4, 2013, pp. 447-457. http://dx.doi.org/10.1016/j.clml.2013.02.019 [15] O. Pritsch, C. Magnac, G. Dumas, C. Egile and G. Dighiero, “V Gene Usage By Seven Hybrids Derived From CD5+ B-Cell Chronic Lymphocytic Leukemia and Dis-Playing Autoantibody Activity,” Blood, Vol. 82, No. 10, 1993, pp. 3103-3112. [16] M. Campbell, A. Zelenetz, A. Levy and R. Levy, “Use of Family Specific Leader Region Primers for PCR Amplification of the Human Heavy Chain Variable Region Gene Repertoire,” Molecular Immunology, Vol. 29, No. 2, 1992, pp. 193-203. http://dx.doi.org/10.1016/0161-5890(92)90100-C [17] C. Moreno and E. Montserrat, “New Prognostic Markers in Chronic Lymphocytic Leukemia,” Blood Reviews, Vol. 22, No. 4, 2008, pp. 211-219. http://dx.doi.org/10.1016/j.blre.2008.03.003 [18] A. Rosenwald, A. A. Alizadeh, D. Widhofp, R. Simon, R. E. Davis, X. Yu, et al., “Relation of Gene Expression Phenotype to Immunoglobulin Mutation Genotype in B Cell Chronic Lymphocytic Leukemia,” Journal of Experimental Medicine, Vol. 194, No. 11, 2001, pp. 1639-1647. http://dx.doi.org/10.1084/jem.194.11.1639 [19] U. Klein, Y. Tu, G. A. Stolovitzky, M. Mattioli, G. Cattoretti, H. Husson, et al., “Gene Expression Profiling of B Cell Chronic Lymphocytic Leukemia Reveals a Homogeneous Phenotype Related to Memory B Cells,” Journal of Experimental Medicine, Vol. 194, No. 11, 2001, pp. 1625-1638. http://dx.doi.org/10.1084/jem.194.11.1625 [20] D. Kienle, A. Benner, C. Laufle, D. Winkler, C. Schneider, A. Bühler, et al., “Gene Expression Factors as Predictors of Genetic Risk and Survival in Chronic Lymphocytic Leukemia,” Haematologica, Vol. 95, No. 1, 2010, pp. 102-109. http://dx.doi.org/10.3324/haematol.2009.010298 [21] C. Mayr, M. R. Speicher, D. M. Kofler, R. Buhmann, J. Strehl, R. Busch, et al., “Chromosomal Translocations Are Associated with Poor Prognosis in Chronic Lymphocytic Leukemia,” Blood, Vol. 107, No. 2, 2006, pp. 742-751. http://dx.doi.org/10.1182/blood-2005-05-2093 [22] E. Van Den Neste, V. Robin, J. Francart, A. Hagemeijer, M. Stul, P. Vandenberghe, et al., “Chromosomal Translocations Independently Predict Treatment Failure, Treatment-Free Survival and Overall Survival in B-Cell Chronic Lymphocytic Leukemia Patients Treated with Cladribine,” Leukemia, Vol. 21, No. 8, 2007, pp. 1715-1722. http://dx.doi.org/10.1038/sj.leu.2404764 [23] A. Travella, L. Ripollés, A. Aventin, A. Rodríguez, R. F. Bezares, M. R. Caballín and I. Slavutsky, “Structural Alterations in Chronic Lymphocytic Leukaemia. Cytogenetic and FISH Analysis,” Hematological Oncology, Vol. 31, No. 2, 2013, pp. 339-347. http://dx.doi.org/10.1002/hon.2025 [24] D. Benedetti, R. Bomben, M. Dal-Bo, D. Marconi, A. Zucchetto, M. Degan, et al., “Are Surrogates of IGHV Gene Mutational Status Useful in B-Cell Chronic Lymphocytic Leukemia? The Example of Septin-10,” Leukemia, Vol. 22, No.1, 2008, pp. 224-226. http://dx.doi.org/10.1038/sj.leu.2404867 [25] M. A. Kaderi, M. Kanduri, A. M. Buhl, M. Sevov, N. Cahill, R. Gunnarsson, et al., “LPL Is the Strongest Prognostic Factor in a Comparative Analysis of RNA-Based Markers in Early Chronic Lymphocytic Leukemia,” Haematologica, Vol. 96, No. 8, 2011, pp. 1153-1160. http://dx.doi.org/10.3324/haematol.2010.039396
[1] N. Chiorazzi, K. R. Rai and M. Ferrarini, “Chronic Lymphocytic Leukemia,” New England Journal of Medicine, Vol. 352, No. 8, 2005, pp. 804-815. http://dx.doi.org/10.1056/NEJMra041720 [2] H. Dohner, S. Stilgenbauer, A. Benner, E. Leupolt, A. Krober, L. Bullinger, et al., “Genomic Aberrations and Survival in Chronic Lymphocytic Leukemia,” New England Journal of Medicine, Vol. 343, No. 26, 2000, pp. 1910-1916. http://dx.doi.org/10.1056/NEJM200012283432602 [3] R. N. Damle, T. Wasil, F. Fais, F. Ghiotto, A. Valetto, S. L. Allen, et al., “Ig V Gene Mutation Status and CD38 Expression as Novel Prognostic Indicators in Chronic Lymphocytic Leukaemia,” Blood, Vol. 94, No. 6, 1999, pp. 1840-1847. [4] T. J. Hamblin, Z. Davis, A. Gardiner, D. G. Oscier and F. K. Stevenson, “Unmutated Ig VH Genes Are Associated with a More Aggressive Form of Chronic Lymphocytic Leukaemia,” Blood, Vol. 94, No. 6, 1999, pp. 1848-1854. [5] P. A. Hall, K. Jung, K. J. Hillan and S. E. Russell, “Expression Profiling the Human Septin Gene Family,” Journal of Pathology, Vol. 206, No. 3, 2005, pp. 269-278. http://dx.doi.org/10.1002/path.1789 [6] M. Liu, S. Shen, F. Chen, W. Yu and L. Yu, “Linking the Septin Expression with Carcinogenesis,” Molecular Biology Reports, Vol. 37, No. 7, 2010, pp. 3601-3608. http://dx.doi.org/10.1007/s11033-010-0009-2 [7] B. E. Kremer, T. Haysted and I. G. Macara, “Mammalian Septins Regulate Microtubule Stability through Interaction with the Microtubule-Binding Protein MAP4”, Molecular Biology of the Cell, Vol. 16, No. 10, 2005, pp. 4648-4659. http://dx.doi.org/10.1091/mbc.E05-03-0267 [8] M. Xu, M. Takanashi, K. Oikawa, H. Nishi, K. Isaka, T. Yoshimoto, et al., “Identification of a Novel Role of Septin 10 in Paclitaxel-Resistance in Cancers through a Functional Genomic Screen,” Cancer Science, Vol. 103, No. 4, 2012, pp. 821-827. http://dx.doi.org/10.1111/j.1349-7006.2012.02221.x [9] M. Bilban, D. Heintel, T. Scharl, T. Woelfel, M. M. Auer, E. Porpaczy, et al., “Deregulated Expression of Fat and Muscle Genes in B-Cell Chronic Lymphocytic Leukemia with High Lipoprotein Lipase Expression,” Leukemia, Vol. 20, No. 6, 2006, pp. 1080-1088. http://dx.doi.org/10.1038/sj.leu.2404220 [10] M. B. Van’t Veer, A. M. Brooijmans, A. W. Langerak, B. Verhaaf, C. S. Goudswaard, W. J. Graveland, et al., “The Predictive Value of Lipoprotein Lipase for Survival in Chronic Lymphocytic Leukemia,” Haematologica, Vol. 91, No. 1, 2006, pp. 56-63. [11] M. Hallek, B. D. Cheson, D. Catovsky, F. Caligaris-Cappio, G. Dighiero, H. Dohner, et al., “Guidelines for the Diagnosis and Treatment of Chronic Lymphocytic Leukemia: A Report from the International Workshop on Chronic Lymphocytic Leukemia Updating the National Cancer Institute-Working Group 1996 Guidelines,” Blood, Vol. 111, No. 12, 2008, pp. 5446-5456. [12] K. R. Rai, A. Sawitsky, E. P. Cronkite, A. D. Chanana, R. N. Levy and B. S. Pasternack, “Clinical Staging of Chronic Lymphocytic Leukemia,” Blood, Vol. 46, No. 2, 1975, pp. 219-234. [13] L. H. Hu, F. H. Chen, Y. R. Li and L. Wang, “Real-Time Determination of Human Telomerase Reverse Transcriptase mRNA in Gastric Cancer,” World Journal of Gastroenterology, Vol. 10, No. 23, 2004, pp. 3514-3517. [14] C. Stanganelli, A. Travella, R. Bezares and I. Slavutsky, “Immunoglobulin Gene Rearrangements and Mutational Status in Argentinean Patients with Chronic Lymphocytic Leukemia,” Clinical Lymphoma Myeloma and Leukemia, Vol. 13, No. 4, 2013, pp. 447-457. http://dx.doi.org/10.1016/j.clml.2013.02.019 [15] O. Pritsch, C. Magnac, G. Dumas, C. Egile and G. Dighiero, “V Gene Usage By Seven Hybrids Derived From CD5+ B-Cell Chronic Lymphocytic Leukemia and Dis-Playing Autoantibody Activity,” Blood, Vol. 82, No. 10, 1993, pp. 3103-3112. [16] M. Campbell, A. Zelenetz, A. Levy and R. Levy, “Use of Family Specific Leader Region Primers for PCR Amplification of the Human Heavy Chain Variable Region Gene Repertoire,” Molecular Immunology, Vol. 29, No. 2, 1992, pp. 193-203. http://dx.doi.org/10.1016/0161-5890(92)90100-C [17] C. Moreno and E. Montserrat, “New Prognostic Markers in Chronic Lymphocytic Leukemia,” Blood Reviews, Vol. 22, No. 4, 2008, pp. 211-219. http://dx.doi.org/10.1016/j.blre.2008.03.003 [18] A. Rosenwald, A. A. Alizadeh, D. Widhofp, R. Simon, R. E. Davis, X. Yu, et al., “Relation of Gene Expression Phenotype to Immunoglobulin Mutation Genotype in B Cell Chronic Lymphocytic Leukemia,” Journal of Experimental Medicine, Vol. 194, No. 11, 2001, pp. 1639-1647. http://dx.doi.org/10.1084/jem.194.11.1639 [19] U. Klein, Y. Tu, G. A. Stolovitzky, M. Mattioli, G. Cattoretti, H. Husson, et al., “Gene Expression Profiling of B Cell Chronic Lymphocytic Leukemia Reveals a Homogeneous Phenotype Related to Memory B Cells,” Journal of Experimental Medicine, Vol. 194, No. 11, 2001, pp. 1625-1638. http://dx.doi.org/10.1084/jem.194.11.1625 [20] D. Kienle, A. Benner, C. Laufle, D. Winkler, C. Schneider, A. Bühler, et al., “Gene Expression Factors as Predictors of Genetic Risk and Survival in Chronic Lymphocytic Leukemia,” Haematologica, Vol. 95, No. 1, 2010, pp. 102-109. http://dx.doi.org/10.3324/haematol.2009.010298 [21] C. Mayr, M. R. Speicher, D. M. Kofler, R. Buhmann, J. Strehl, R. Busch, et al., “Chromosomal Translocations Are Associated with Poor Prognosis in Chronic Lymphocytic Leukemia,” Blood, Vol. 107, No. 2, 2006, pp. 742-751. http://dx.doi.org/10.1182/blood-2005-05-2093 [22] E. Van Den Neste, V. Robin, J. Francart, A. Hagemeijer, M. Stul, P. Vandenberghe, et al., “Chromosomal Translocations Independently Predict Treatment Failure, Treatment-Free Survival and Overall Survival in B-Cell Chronic Lymphocytic Leukemia Patients Treated with Cladribine,” Leukemia, Vol. 21, No. 8, 2007, pp. 1715-1722. http://dx.doi.org/10.1038/sj.leu.2404764 [23] A. Travella, L. Ripollés, A. Aventin, A. Rodríguez, R. F. Bezares, M. R. Caballín and I. Slavutsky, “Structural Alterations in Chronic Lymphocytic Leukaemia. Cytogenetic and FISH Analysis,” Hematological Oncology, Vol. 31, No. 2, 2013, pp. 339-347. http://dx.doi.org/10.1002/hon.2025 [24] D. Benedetti, R. Bomben, M. Dal-Bo, D. Marconi, A. Zucchetto, M. Degan, et al., “Are Surrogates of IGHV Gene Mutational Status Useful in B-Cell Chronic Lymphocytic Leukemia? The Example of Septin-10,” Leukemia, Vol. 22, No.1, 2008, pp. 224-226. http://dx.doi.org/10.1038/sj.leu.2404867 [25] M. A. Kaderi, M. Kanduri, A. M. Buhl, M. Sevov, N. Cahill, R. Gunnarsson, et al., “LPL Is the Strongest Prognostic Factor in a Comparative Analysis of RNA-Based Markers in Early Chronic Lymphocytic Leukemia,” Haematologica, Vol. 96, No. 8, 2011, pp. 1153-1160. http://dx.doi.org/10.3324/haematol.2010.039396