Background: High levels of MCL-1 and BCL-2 proteins have been found in Chronic Lymphocytic Leukemia (CLL), and inversely correlated with response to treatment. BCL-2/Bax ratio is the main director of apoptosis in CLL. The study aimed to clarify the prognostic role of MCL-1, BCL-2 and BCL-2/ Bax ratio in B-CLL. Patients & method: Estimation of MCL-1, BCL-2 and Bax expressions by a flow cytometry in 45 B-CLL patients and the prognostic value of these markers were correlated with other well-known established prognostic markers and treatment response. Results: MCL-1 was expressed in 60% of cases while BCL-2 was expressed in 82.2% of cases. MCL-1 expression was significantly high in male gender, short lymphocyte doubling time (LDT), and high expression of CD 38 ( p < 0.001). High (Serum LDH, serum β 2M, CD38 expression), low ZAP-70 expression, splenomegaly and higher Rai stage were significantly increased in patients with high expression of BCL-2 ( p < 0.001); also a significant decrease in (HB level, platelet count), and increase in serum LDH, serum β 2M, high C-D38 expression, low ZAP-70 expression, the poor cytogenetic and splenomegaly in patients with high expression of BCL-2/ Bax ratio ( p < 0.001). Among the 39 patients who started treatment when indicated responding patients had statistically significant lower BCL-2/Bax ratio than non-responding patients, although their lower mean of MCL-1 and BCL2 expressions values were insignificant. In conclusion: MCL-1, BCL-2 expressions and BCL-2/Bax ratio could be useful potential predictive and prognostic markers in B-CLL.
Rozman, C. and Montserrat, E. (1995) Chronic Lymphocytic Leukemia. The New England Journal of Medicine, 333, 1052-1057. https://doi.org/10.1056/NEJM199510193331606
Chiorazzi, N., Rai, K.R. and Ferrarini, M. (2005) Chronic Lymphocytic Leukemia. The New England Journal of Medicine, 352, 804-815. https://doi.org/10.1056/NEJMra041720
Krober, A., Seiler, T., Benner, A., Bullinger, L., Bruckle, E., Lichter, P., et al. (2002) V(H) Mutation Status, CD38 Expression Level, Genomic Aberrations, and Survival in Chronic Lymphocytic Leukemia. Blood, 100, 1410-1416.
Kipps, T.J. (1997) Chronic Lymphocytic Leukemia. Current Opinion in Hematology, 4, 268-276. https://doi.org/10.1097/00062752-199704040-00008
Caligaris-Cappio, F. (1996) B-Chronic Lymphocytic Leukemia: A Malignancy of Anti-Self B Cells. Blood, 87, 2615-2620.
Pepper, C., Hooper, K., Thomas, A., et al. (2001) BCL-2 Antisense Oligonucleotides Enhance the Cytotoxicity of Chlorambucil-Induced Apoptosis in Chronic Lymphocytic Leukemia. Leukemia & Lymphoma, 42, 491-498. https://doi.org/10.3109/10428190109064606
Scarfò, L. and Ghia, P. (2013) Reprogramming Cell Death: BCL2 Family Inhibition in Hematological Malignancies. Immunology Letters, 155, 36-39. https://doi.org/10.1016/j.imlet.2013.09.015
Cimmino, A., Calin, G.A., Fabbri, M., et al. (2005) miR-15 and miR-16 Induce Apoptosis by Targeting BCL2. Proceedings of the National Academy of Sciences of the United States of America, 102, 13944-13949. https://doi.org/10.1073/pnas.0506654102
Pepper, C., Hoy, T. and Bentley, P. (1998) Elevated BCL-2/Bax Are a Consistent Feature of Apoptosis Resistance in B-Cell Chronic Lymphocytic Leukemia and Are Correlated with in Vivo Chemoresistance. Leukemia & Lymphoma, 28, 355-361. https://doi.org/10.3109/10428199809092690
Korsmeyer, S.J., Shutter, J.R., Veis, D.J., Merry, D.E. and Oltvai, Z.N. (1993) BCL-2/ Bax: A Rheostat That Regulates an Anti-Oxidant Pathway and Cell Death. Seminars in Cancer Biology, 4, 327-332.
Pepper, C., Bentley, P. and Hoy, T. (1996) Regulation of Clinical Chemoresistance by BCL-2 and Bax Oncoproteins in B-Cell Chronic Lymphocytic Leukemia. British Journal of Haematology, 95, 513-517. https://doi.org/10.1046/j.1365-2141.1996.d01-1927.x
Thomas, A., El Rouby, S., Reed, J.C., Krajewski, S., Silber, R., Potmesil, M., et al. (1996) Drug Induced Apoptosis in B-Cell Chronic Lymphocytic Leukemia: Relationship between p53 Gene Mutation and BCL-2/Bax Proteins in Drug Resistance. Oncogene, 12, 1055-1062.
Pepper, C., Hoy, T. and Bentley, D.P. (1997) BCL-2/Bax Ratios in Chronic Lymphocytic Leukaemia and Their Correlation with in Vitro Apoptosis and Clinical Resistance. British Journal of Cancer, 76, 935-938. https://doi.org/10.1038/bjc.1997.487
Klobusicka, M., Kusenda, J. and Babusikova, O. (2002) Immunocytochemical Detection of BCL-2 and p53 Proteins in B-Chronic Lymphocytic Leukemia Patients. Neoplasma, 49, 387-397.
Anurage Saxena, A., Viswanathan, S., Moshynska, O., et al. (2004) MCL-1 and BCL-2/Bax Ratio Are Associated with Treatment Response but Not with Rai Stage in B-Cell Chronic Lymphocytic Leukemia. American Journal of Hematology, 75, 22-33. https://doi.org/10.1002/ajh.10453
Srinivas, G., Kusumary, P., Krishnav, M., et al. (2000) Mutant p53 Protein, BCL-2/ Bax Ratio and Apoptosis in Pediatric Acute Lymphoblastic Leukemia. Journal of Cancer Research and Clinical Oncology, 126, 62-67. https://doi.org/10.1007/s004320050010
Cheson, B.D., Bennett, J.M., Grever, M., Kay, N., Keating, M.J., O’Brien, S., et al. (1996) National Cancer Institute-Sponsored Working Group Guidelines for Chronic Lymphocytic Leukemia: Revised Guidelines for Diagnosis and Treatment. Blood, 87, 4990-4997.
Zenz, T., Hling, S.F., Mertens, D., Dohner, H. and Stilgenbauer, S. (2010) Moving from Prognostic to Predictive Factors in Chronic Lymphocytic Leukaemia (CLL). Best Practice Research: Clinical Haematology Home, 23, 71-84. https://doi.org/10.1016/j.beha.2009.12.003
Hochenbery, D., Nunez, G., Milliman, C., et al. (1990) BCL-2 Is an Inner Mitochondrial Membrane Protein That Blocks Programmed Cell Death. Nature, 348, 334-336. https://doi.org/10.1038/348334a0
Bissonnette, R.P., Echeverri, F., Mahboubi, A., et al. (1992) Apoptotic Cell Death Induced by c-myc Is Inhibited by bcl-2. Nature, 359, 552-554. https://doi.org/10.1038/359552a0
Opferman, J.T., Letai, A., Beard, C., et al. (2003) Development and Maintenance of B and T Lymphocytes Requires Antiapoptotic MCL-1. Nature, 426, 671-676. https://doi.org/10.1038/nature02067
Kitada, S., Andersen, J., Akar, S., Zapata, J.M., Takayama, S., Krajewski, S., et al. (1998) Expression of Apoptosis-Regulating Proteins in Chronic Lymphocytic Leukemia: Correlations with in Vitro and in Vivo Chemoresponses. Blood, 91, 3379-3389.
Lomo, J., Smeland, E.B., Krajewski, S., Reed, J.C. and Blomhoff, H.K. (1996) Expression of the BCL-2 Homologue MCL-1 Correlates with Survival of Peripheral Blood B Lymphocytes. Cancer Research, 56, 40-43.
Moshynska, O., Sheridan, D.P., Kanthan, R. and Saxena, A. (2002) MCL-1 Gene Nucleotide Replacements in B-Cell Chronic Lymphocytic Leukemia. Laboratory Investigation, 82, 256A (abstract 1066).
Marschitz, I., Tinhofer, I., Hittmair, A., et al. (2000) Analysis of BCL-2 Protein Expression in Chronic Lymphocytic Leukemia. A Comparison of Three Semiquantitation Techniques. American Journal of Clinical Pathology, 113, 219-229. https://doi.org/10.1309/491W-L1TN-UFQX-T61B
Kitada, S., Anderson, J., Akar, S., et al. (1998) Expression of Apoptosis-Regulating Proteins in Chronic Lymphocytic Leukemia: Correlations with in Vitro and in Vivo Chemoresponses. Blood, 91, 3379-3389.
Lazaridou, A., Miraxtsi, C., Korantzis, J., et al. (2000) Simultaneous Detection of BCL-2 Protein, Trisomy 12, Retinoblastoma and P53 Monoallelic Gene Deletions in B-Cell Chronic Lymphocytic Leukemia by Fluorescence in Situ Hybridization (FISH): Relation to Disease Status. Leukemia & Lymphoma, 36, 503-512. https://doi.org/10.3109/10428190009148398
Mendez, P., Vargas, A., Bueno, C., et al. (2004) Quantitative Analysis of BCL-2 Expression in Normal and Leukemic Human B-Cell Differentiation. Leukemia, 18, 491-198.
Schimmer, A.D., Munk-Pederson, I., Minden, M.D., et al. (2003) BCL-2 and Apoptosis in Chronic Lymphocytic Leukemia. Current Treatment Options in Oncology, 4, 211-218. https://doi.org/10.1007/s11864-003-0022-y
Del Poeta, G., Del Principe, M.I., Maurillo, L., et al. (2010) Spontaneous Apoptosis and Proliferation Detected by BCL-2 and CD71 Proteins Are Important Progression Indicators within ZAP-70 Negative Chronic Lymphocytic Leukemia. Leukemia & Lymphoma, 51, 95-106. https://doi.org/10.3109/10428190903350421
Damle, R.N., Wasil, T., Fais, F., et al. (1999) Ig V Gene Mutation Status and CD38 Expression as Novel Prognostic Indicators in Chronic Lymphocytic Leukemia. Blood, 94, 1840-1847.
Pepper, C., Thomas, A., Hoy, T. and Bentley, P. (1999) Chlorambucil Resistance in B-Cell Chronic Lymphocytic Leukaemia Is Mediated through Failed Bax Induction and Selection of High BCL-2-Expressing Subclones. British Journal of Haematology, 104, 581-588. https://doi.org/10.1046/j.1365-2141.1999.01210.x
Klein, A., Miera, O., Bauer, O., Golfier, S. and Schriever, F. (2000) Chemosensitivity of B Cell Chronic Lymphocytic Leukemia and Correlated Expression of Proteins Regulating Apoptosis, Cell Cycle and DNA Repair. Leukemia, 14, 40-46. https://doi.org/10.1038/sj.leu.2401636
Thomas, A., Pepper, C., Hoy, T. and Bentley, P. (2000) BCL-2 and Bax Expression and Chlorambucil-Induced Apoptosis in the T Cells and Leukaemic B-Cells of Untreated B-Cell Chronic Lymphocytic Leukaemia Patients. Leukemia Research, 24, 813-821. https://doi.org/10.1016/S0145-2126(00)00051-5
Stoetzer, O.J., Pogrebniak, A., Scholz, M., Pelka-Fleischer, R., Gullis, E., Darsow, M., et al. (1999) Drug-Induced Apoptosis in Chronic Lymphocytic Leukemia. Leukemia, 13, 1873-1880. https://doi.org/10.1038/sj.leu.2401572
Zaja, F., Di Loreto, C., Amoroso, V., Salmaso, F., Russo, D., Silvestri, F., et al. (1998) BCL-2 Immunohistochemical Evaluation in B-Cell Chronic Lymphocytic Leukemia and Hairy Cell Leukemia before Treatment with Fludarabine and 2-Chlorodeoxyadenosine. Leukemia & Lymphoma, 28, 567-572. https://doi.org/10.3109/10428199809058365