apoptosis

Autophagy: cell death or survival strategy?

REVIEWS , ,

O.V. Kovaleva, M.S. Shitova, and I.B. Zborovskaya

N.N. Blokhin Russian Cancer Research Center, RAMS, Moscow, Russian Federation

ABSTRACT

The interaction between proliferation, differentiation, and programmed cell death is an integral part of the life-sustaining activity of multicellular organisms. The imbalance between these processes underlies the development of many human diseases. Understanding molecular mechanisms of these processes is important for identifying new diagnostic and therapeutic targets. During the last decade, the autophagy processed and its role in the cell life and death became a subject of great scientific interest. Autophagy represents a mechanism of intracellular substance utilization. Autophagy is a process that occurs in all cells under normal conditions. But under certain circumstances, this process can result in the cell death. Impaired autophagy significantly contributes into the development of some diseases (cancer, neurodegenerative and cardiovascular disorders etc.).

Keywords: apoptosis, autophagy, carcinogenesis

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REFERENCES

  1. Galluzzi L., Vitale I., Abrams J.M. et al. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ. 2012; 19(1): 107–20.
  2. Kerr J.F., Wyllie A.H., Currie A.R. Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 1972; 26: 239–57.
  3. Wong R.S. Apoptosis in cancer: from pathogenesis to treatment. J. Exp. Clin. Cancer Res. 2011; 26: 30–87.
  4. Hu Y., Benedict M.A., Ding L., Nunez G. Role of cytochrome c and dATP/ ATP hydrolysis in Apaf-1-mediated caspase-9 activation and apoptosis. EMBO J. 1999; 18: 3586–95.
  5. Saelens X., Festjens N., Vande Walle L. et al. Toxic proteins released from mitochondria in cell death. Oncogene 2004; 23(16): 2861–74.
  6. Altieri D.C. Surviving in apoptosis control and cell cycle regulation in cancer. Prog. Cell Cycle Res. 2003; 5: 447–52.
  7. Tamm I., Wang Y., Sausville E. et al. IAP-family protein surviving inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs. Cancer Res. 1998; 58(23): 5315–20.
  8. Padanilam B.J. Cell death induced by acute renal injury: a perspective on the contributions of apoptosis and necrosis. Am. J. Physiol. Renal. Physiol. 2003; 284(4): F608–27.
  9. Hoste E., Kemperman P., Devos M. et al. Caspase-14 is required for filaggrin degradation to natural moisturizing factors in the skin. J. Invest. Dermatol. 2011; 131(11): 2233–41.
  10. Levine B., Klionsky D.J. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev. Cell 2004; 6(4): 463–77.
  11. Okada H., Mak T.W. Pathways of apoptotic and non-apoptotic death in tumor cells. Nat. Rev. Cancer 2004; 4(8): 592–603.
  12. Kaminskyy V., Zhivotovsky B. Proteases in autophagy. Biochimica er Biophysica Acta. 2012; 1824: 44–50.
  13. Mijaljica D., Prescott M., Devenish R.J. Microautophagy in mammalian cells: Revisiting a 40-year-old conundrum. Autophagy 2011; 7: 673–82.
  14. Klionsky DJ., Codogno P., Cuervo A.M. et al. A comprehensive glossary of autophagy-related molecules and processes. Autophagy 2010; 6(4): 438–48.
  15. Massey A.C., Zhang C., Cuervo A.M. Chaperone-mediated autophagy in aging and disease. Curr. Top. Dev. Biol. 2006; 73: 205–35.
  16. Kimmelman A.C. The dynamic nature of autophagy in cancer. Genes Dev. 2011; 25(19): 1999–2010.
  17. Reggiori F., Tucker K.A., Stromhaug P.E., Klionsky D.J. The Atg1-Atg13 complex regulates Atg9 and Atg23 retrieval transport from the pre-autophagosomal structure. Dev. Cell 2004; 6(1): 79–90.
  18. Wang C.W., Klionsky D.J. The molecular mechanism of autophagy. Mol. Med. 2003; 9: 65–76.
  19. Teter S.A., Klionsky D.J. Transport of proteins to the yeast vacuole: autophagy, cytoplasm-to-vacuole targeting, and role of the vacuole in degradation. Semin. Cell Dev. Biol. 2000; 11(3): 173–9.
  20. Chen N., Debnath J. Autophagy and Tumorigenesis. FEBS Lett. 2010; 584(7): 1427–35.
  21. Guertin D.A., Sabatini D.M. Defining the role of mTOR in cancer. Cancer Cell 2007; 12: 9–22.
  22. He C., Klionsky D.J. Regulation Mechanisms and Signaling Pathways of Autophagy. Annu. Rev. Genet. 2009; 43: 67–93.
  23. Zhou H., Huang S. The complexes of mammalian target of rapamycin. Curr. Protein Pept. Sci. 2010; 11: 409–24.
  24. Teter T., Hall M.N. TOR, a central controller of cell growth. Cell 2000; 103(2): 253–62.
  25. Tee A.R., Manning B.D., Roux P.P., Cantley L.C., Blenis J. Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr. Biol. 2003; 13: 1259–68.
  26. Shackelford D.B., Shaw R.J. The LKB1-AMPK pathway: metabolism and growth control in tumor suppression. Nat. Rev. Cancer 2009; 9: 563–75.
  27. Liang J., Shao SH., Xu Z.X. et al. The energy sensing LKB1-AMPK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis. Nat. Cell Biol. 2007; 9: 218–24.
  28. Feng Z., Hu W., Stanchina E. et al. The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways. Cancer Res. 2007; 67: 3043–53.
  29. Mortensen M., Watson A.S., Simon A.K. Lack of autophagy in the hematopoietic system leads to loss of hematopoietic stem cell function and dysregulated myeloid proliferation. Autophagy 2011; 7(9): 1069–70.
  30. Mortensen M., Soilleux E.J., Djordjevic G. et al. The autophagy protein Atg7 is essential for hematopoietic stem cell maintenance. J. Exp. Med. 2011; 208: 455–67.
  31. Pua H.H., Komatsu M., He Y.W. Autophagy is essential for mitochondrial clearance in mature T lymphocytes. J. Immunol. 2009; 182: 4046–55.
  32. Pua H.H., Dzhagalov I., Chuck M. et al. A critical role for the autophagy gene Atg5 in T cell survival and proliferation. J. Exp. Med. 2007; 204: 25–31.
  33. Pua H.H., He Y.W. Maintaining T lymphocyte homeostasis: another duty of autophagy. Autophagy 2007; 3: 266–7.
  34. Miller B.C., Zhao Z., Stephenson L.M. et al. The autophagy gene Atg5 plays an essential role in B lymphocyte development. Autophagy 2008; 4: 309–14.
  35. Novak I., Kirkin V., McEwan D.G. et al. Nix is a selective autophagy receptor for mitochondrial clearance. EMBO Rep. 2010; 11(1): 45–51.
  36. Kundu M., Lindsten T., Yang C.Y. et al. Ulk1 plays a critical role in the autophagic clearance of mitochondria and ribosomes during reticulocyte maturation. Blood 2008; 112: 1493–502.
  37. Raslova H., Kauffmann A., Sekkai D. et al. Interrelation between polyploidization and megakaryocyte differentiation: a gene profiling approach. Blood. 2007; 109: 3225–34.
  38. Delgado M.A., Elmaoued R.A., Davis A.S., Kyei G., Deretic V. Toll-like receptors control autophagy. EMBO J. 2008; 27: 1110–21.
  39. Shi C.S., Kehrl J.H. MyD88 and Trif target Beclin 1 to trigger autophagy in macrophages. J. Biol. Chem. 2008; 283: 33175–82.
  40. Xu Y., Jagannath C., Liu X.D. et al. Toll-like receptor 4 is a sensor for autophagy associated with innate immunity. Immunity. 2007; 27: 135–44.
  41. Канцерогенез. Под ред. Д.Г. Заридзе. М.: Медицина, 2004. [Kantserogenez. Pod red. D.G. Zaridze (Carcinogenesis. Ed. by: D.G. Zaridze). M.: Meditsina, 2004.]
  42. Liang X.H., Jackson S., Seaman M. et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 1999; 402: 672–6.
  43. Yue Z., Jin S., Yang C., Levine A.J., Heintz N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc. Natl. Acad. Sci. U S A 2003; 100: 15077–82.
  44. Qu X., Yu J., Bhagat G. et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J. Clin. Invest. 2003; 112: 1809–20.
  45. Karantza-Wadsworth V., Patel S., Kravchuk O. et al. Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev. 2007; 21: 1621–35.
  46. Meek D.W. Tumor suppression by p53: a role for the DNA damage response? Nat. Rev. Cancer 2009; 9: 714–23.
  47. Degenhardt K., Mathew R., Beaudoin B. et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 2006; 10: 51–64.
  48. DeNardo D., Johansson M., Coussens L. Immune cells as mediators of solid tumor metastasis. Cancer Metast. Rev. 2008; 27: 11–8.
  49. DeNardo D.G., Barreto J.B., Andreu P. et al. CD4+ T Cells Regulate Pulmonary Metastasis of Mammary Carcinomas by Enhancing Protumor Properties of Macrophages. Cancer Cell 2009; 16: 91–102.
  50. Bingle L., Brown N.J., Lewis C.E. The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J. Pathol. 2002; 196: 254–65.
  51. Young A.R., Narita M., Ferreira M. et al. Autophagy mediates the mitotic senescence transition. Genes Dev. 2009; 23: 798–803.
  52. Petiot A., Ogier-Denis E., Blommaart E.F., Meijer AJ., Codogno P. Distinct classes of phosphatidylinositol 3¢-kinases are involved in signaling pathways that control macroautophagy in HT-29 cells. J. Biol. Chem. 2000; 275: 992–8.
  53. Luiken J.J., Aerts J.M., Meijer A.J. The role of the intralysosomal pH in the control of autophagic proteolytic flux in rat hepatocytes. Eur. J. Biochem. 1996; 235: 564–73.
  54. Yamamoto A., Tagawa Y., Yoshimori T. et al. Bafilomycin A1 prevents maturation of autophagic vacuoles by inhibiting fusion between autophagosomes and lysosomes in rat hepatoma cell line, H-4-II-E cells. Cell Struct. Funct. 1998; 23: 33–42.
  55. Ito H., Daido S., Kanzawa T., Kondo S., Kondo Y. Radiation-induced autophagy is associated with LC3 and its inhibition sensitizes malignant glioma cells. Int. J. Oncol. 2005; 26: 1401–10.
  56. Lomonaco S.L., Finniss S., Xiang C. et al. The induction of autophagy by gamma-radiation contributes to the radioresistance of glioma stem cells. Int. J. Cancer 2009; 125: 717–22.
  57. Shingu T., Fujiwara K., Bogler O. et al. Stage-specific effect of inhibition of autophagy on chemotherapy-induced cytotoxicity. Autophagy 2009; 5: 537–9.
  58. Vazquez-Martin A., Oliveras-Ferraros C., Menendez J.A. Autophagy facilitates the development of breast cancer resistance to the anti-HER2 monoclonal antibody trastuzumab. PLoS One 2009; 4: e6251.
  59. Abedin M.J., Wang D., McDonnell M.A., Lehmann U., Kelekar A. Autophagy delays apoptotic death in breast cancer cells following DNA damage. Cell Death Differ. 2007; 14: 500–10.
  60. Kim R.H., Coates J.M., Bowles T.L. et al. Arginine deiminase as a novel therapy for prostate cancer induces autophagy and caspase-independent apoptosis. Cancer Res. 2009; 69: 700–8.
  61. Bellodi C., Lidonnici M.R., Hamilton A. et al. Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosomepositive cells, including primary CML stem cells. J. Clin. Invest. 2009; 119: 1109–23.
  62. Carew J.S., Nawrocki S.T., Kahue C.N. et al. Targeting autophagy augments the anticancer activity of the histone deacetylase inhibitor SAHA to overcome Bcr-Abl-mediated drug resistance. Blood 2007; 10: 313–22.
  63. Ertmer A., Huber V., Gilch S. et al. The anticancer drug imatinib induces cellular autophagy. Leukemia 2007; 21: 936–42.
  64. Kamitsuji Y., Kuroda J., Kimura S. et al. The Bcr-Abl kinase inhibitor INNO-406 induces autophagy and different modes of cell death execution in Bcr-Abl-positive leukemias. Cell Death Differ. 2008; 15: 1712–22.
  65. Goussetis D.J., Altman J.K., Glaser H. et al. Autophagy is a critical mechanism for the induction of the antileukemic effects of arsenic trioxide. J. Biol. Chem. 2010; 285: 29989–97.
  66. Qian W., Liu J., Jin J. et al. Arsenic trioxide induces not only apoptosis but also autophagic cell death in leukemia cell lines via up-regulation of Beclin-1. Leuk. Res. 2007; 31: 329–39.
  67. Charoensuk V., Gati WP., Weinfeld M. et al. Differential cytotoxic effects of arsenic compounds in human acute promyelocytic leukemia cells. Toxicol. Appl. Pharmacol. 2009; 239: 64–70.
  68. Chiarini F., Grimaldi C., Ricci F. et al. Activity of the novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVPBEZ235 against T-cell acute lymphoblastic leukemia. Cancer Res. 2010; 70: 8097–107.
  69. Crazzolara R., Bradstock K.F., Bendall L.J. RAD001 (everolimus) induces autophagy in acute lymphoblastic leukemia. Autophagy 2009; 5: 727–8.
  70. Crazzolara R., Cisterne A., Thien M. et al. Potentiating effects of RAD001 (everolimus) on vincristine therapy in childhood acute lymphoblastic leukemia. Blood 2009; 113: 3297–306.
  71. Puissant A., Auberger P. AMPK- and p62/SQSTM1-dependent autophagy mediate resveratrol-induced cell death in chronic myelogenous leukemia. Autophagy 2010; 6(5): 655–7.
  72. Puissant A., Robert G., Fenouille N. et al. Resveratrol promotes autophagic cell death in chronic myelogenous leukemia cells via JNK mediated p62/SQSTM1 expression and AMPK activation. Cancer Res. 2010; 70: 1042–52.
  73. Kroemer G., Levine B. Autophagic cell death: the story of a misnomer. Nat. Rev. Mol. Cell Biol. 2008; 9: 1004–10.
  74. Turcotte S., Chan D.A., Sutphin P.D. et al. A molecule targeting VHLdeficient renal cell carcinoma that induces autophagy. Cancer Cell. 2008; 14: 90–102.
  75. Kanzawa T., Germano I.M., Komata T. et al. Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells. Cell Death Differ. 2004; 11: 448–57.

Apoptotic markers in CD34-positive cells in acute leukemias

CLINICAL PRESENTATION, DIAGNOSIS, AND MANAGEMENT OF LYMPHOID MALIGNANCIES , , , ,

Ye.N. Parovichnikova1, Ye.Ye. Khodunova1, I.V. Galtseva1, S.М. Kulikov1, V.V. Troitskaya1, L.А. Kuzmina1, D.V. Shcheblyakov2, and V.G. Savchenko1

1 Hematology Research Center, RF Ministry of Health, Moscow, Russian Federation

2 N.F. Gamaleya Research Institution of Epidemiology and Microbiology, RF Ministry of Health, Moscow, Russian Federation

ABSTRACT

Objective. To evaluate expression of Bcl-2, Bax, p53, CD95, and ACE on CD34+ cells of peripheral blood and bone marrow during induction chemotherapy in the patients with newly diagnosed acute leukemia.

Materials and methods. Expression of Bcl-2, Bax, p53, CD95, and ACE on CD34+ cells of the peripheral blood and bone marrow in 23 patients with AL (14 AML and 9 ALL) was measured using flow cytometry analysis. Peripheral blood and bone marrow samples were analyzed before chemotherapy and during the induction course: on Days +8, +21 (blood only), and +36–38. The control group consisted of 8 healthy donors.

Results. Bcl-2 expression on CD34+ sells in BM was 34.8 ± 6 % and significantly higher compared to the donors (11.5 ± 1.8 %) at the time of diagnosis. On Days +36–38 after the onset of chemotherapy, no significant difference between the patients and control groups were found. CD34/Bax coexpression in BM cells of ALL patients was significantly higher than in AML patients and donors. ACE and p53 expression on CD34+ cells in AL patients before and during chemotherapy was significantly lower than in the donors. CD34/ACE coexpression in PB and BM cells of AL patients and donors showed no significant differences at any time-points of evaluation.

Conclusion. The above changes suggest the imbalance between the pro- and anti-apoptotic proteins in AL patients. After chemotherapy, the expression profile of these proteins considerably changed, but did not reach the healthy donor values.

Keywords: acute leukemias, apoptosis, expression of Bcl-2, Bax, р53, CD95, and ACE.

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Refernces

  1. Hengartner M.O. The biochemistry of apoptosis. Nature 2000; 407(6805): 770–6.
  2. Lodish H., Berk A., Matsudaira P. et al. Molecular cell biology, 5th edn. New York: W.H. Freeman and Company, 2003: 961.
  3. Salminen A., Ojala J., Kaarniranta K. Apoptosis and aging: increased resistance to apoptosis enhances the aging process. Cell. Mol. Life Sci. 2011; 68(6): 1021–31.
  4. Spencer S.L., Sorger P.K. Measuring and modeling apoptosis in single cells. Cell 2011; 144(6): 926–39.
  5. Herr I., Debatin K.-M. Cellular stress response and apoptosis in cancer therapy. Blood 2001; 98(9): 2603–14.
  6. Chao D.T., Korsmeyer S. J. BCL-2 family: regulators of cell death. Ann. Rev. Immunol. 1998; 16: 395–419.
  7. Green D.R. Apoptotic pathways: The roads to ruin. Cell 1998; 94: 695–8.
  8. Chauncey T.R. Drug resistance mechanisms in acute leukemia. Curr. Opin. Oncol. 2001; 13(1): 21–6.
  9. Del Poeta G., Bruno A., Del M.I. Principe et al. Deregulation of the mitochondrial apoptotic machinery and development of molecular targeted drugs in acute myeloid leukemia. Curr. Cancer Drug Targets 2008; 8(3): 202–7.
  10. Testa U., Riccioni R. Deregulation of apoptosis in acute myeloid leukemia. Haematologica 2007; 92(1): 81–94.
  11. Banker D.E., Groudine M., Norwood T., Appelbaum F.R. Measurement of spontaneous and therapeutic agent-induced apoptosis with BCL-2 protein expression in acute myeloid leukemia. Blood 1997; 89(1): 243–55.
  12. Stijn A., Pol M.A., Kok A. et al. Differences between the CD34+ and CD34– blast compartments in apoptosis resistance in acute myeloid leukemia. Haematologica 2003; 88(5): 497–508.
  13. Fulda S., Los M., Friesen C., Debatin K.M. Chemosensitivity of solid tumor cells in vitro is related to activation of the CD95 system. Int. J. Cancer 1998; 76(1): 105–14.
  14. Fulda S., Sieverts H., Friesen C. et al. The CD95 (APO-1/Fas) system mediates drug-induced apoptosis in neuroblastoma cells. Cancer Res. 1997; 57(17): 3823–9.
  15. Барышников А.Ю., Полосухина Е.Р., Шишкин Ю.В. и др. Новый прогностический маркер острого лимфобластного лейкоза — антиген CD95 (FAS/APO-1). Гематол. и трансфузиол. 1998; 2: 8–11. [Baryshnikov A.Yu., Polosukhina Ye.R., Shishkin Yu.V. i dr. Novyy prognosticheskiy marker ostrogo limfoblastnogo leykoza — antigen CD95 (FAS/APO-1) (New prognostic marker of acute lymphoblastic leukemia — CD95 antigen (FAS/ APO-1). In: Hematol. & transfusiol.) Gematol. i transfuziol. 1998; 2: 8–11.]
  16. Molica S., Mannella A., Dattilo A. et al. Differential expression of BCL-2 oncoprotein and Fas antigen on normal peripheral blood and leukemic bone marrow cells. A flow cytometric analysis. Haematologica 1996; 81(4): 302–9.
  17. Greenblatt M.S., Bennett W.P., Hollstein M., Harris C.C. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 1994; 54(18): 4855–78.
  18. Ko L.J., Prives C. p53: puzzle and paradigm. Genes & Dev. 1996; 10(9): 1054–72.
  19. Levine A.J. p53, the cellular gatekeeper for growth and division. Cell 1997; 88(3): 323–31.
  20. Resnick M.A., Tomso D., Inga A. et al. Functional diversity in the gene network controlled by the master regulator p53 in humans. Cell. Cycle 2005; 4(8): 1026–9.
  21. Prokocimer M., Rotter V. Structure and function of p53 in normal cells and their aberrations in cancer cells: projection on the hematologic cell lineages. Blood 1994; 84(8): 2391–411.
  22. Wada M., Bartram C.R., Nakamura H. et al. Analysis of p53 mutations in a large series of lymphoid hematologic malignancies of childhood. Blood 1993; 82(10): 3163–9.
  23. Cavalcanti G.B., Scheiner M.A., Simoes Magluta E.P. et al. p53 flow cytometry evaluation in leukemias: correlation to factors affecting clinical outcome. Cytometry B. Clin. Cytom. 2010; 78(4): 253–9.
  24. Beyazit Y., Aksu S., Haznedaroglu I.C. et al. Overexpression of the local bone marrow renin-angiotensin system in acute myeloid leukemia. J. Natl. Med. Assoc. 2007; 99: 57–63.
  25. Goker H., Haznedaroglu I.C., Beyazit Y. et al. Local umbilical cord blood renin-angiotensin system. Ann. Hematol. 2005; 84: 277–81.
  26. Jokubaitis V.J., Sinka L., Driessen R. et al. Angiotensin-converting enzyme (CD143) marks hematopoietic stem cells in human embryonic, fetal, and adult hematopoietic tissues. Blood 2008; 111: 4055–63.
  27. Li J., Volkov L., Comte L. et al. Production and consumption of the tetrapeptide AcSDKP, a negative regulator of hematopoietic stem cells, by hematopoietic microenvironmental cells. Exp. Hematol. 1997; 25: 140–6.
  28. Гальцева И.В., Пашин Л.Е., Савченко В.Г. Лейкемические дендритные клетки. Тер. арх. 2008; 80(7): 84–8. [Galtseva I.V., Pashin L.Ye., Savchenko V.G. Leykemicheskiye dendritnyye kletki (Leukemic dendritic cells. In: Ther. archive). Ter. arkh. 2008; 80(7): 84–8.]
  29. Danilov S.M., Sadovnikova E., Scharenborg N. et al. Angiotensinconverting enzyme (CD 143) is abundantly expressed by dendritic cells and discriminates human monocyte-derived dendritic cells from acute myeloid leukemia-derived dendritic cells. Exp. Hematol. 2003; 31(12): 1301–9.
  30. Del Poeta G., Venditti A., Del Principe M.I. et al. Amount of spontaneous apoptosis detected by Bax/Bcl-2 ratio predicts outcome in acute myeloid leukemia (AML). Blood 2003; 101(6): 2125–31.
  31. El-Manallawy H.A., El-Shkankiry N.H., El-Guindy S. et al. The Expression of Bcl-2 and Bax Proteins and Their Clinical Relevance in ALL and CLL Patients. J. Egypt. Nat. Cancer Inst. 2001; 13(1): 35–42.
  32. Hogarth L.A., Hall A.G. Increased BAX expression is associated with an increased risk of relapse in childhood acute lymphocytic leukemia. Blood 1999; 93(8): 2671–8.
  33. Aksu S., Beyazit Y., Haznedaroglu I.C. et al. Enhanced expression of the local haematopoietic bone marrow renin-angiotensin system in polycythemia rubra vera. J. Int. Med. Res. 2005; 33(6): 661–7.
  34. Aksu S., Beyazit Y., Haznedaroqlu I.C. et al. Over-expression of angiotensin-converting enzyme (CD 143) on leukemic blasts as a clue for the activated local bone marrow RAS in AML. Leuk. Lymphoma 2006; 47(5): 891–6.
  35. Барышников А.Ю., Шишкин Ю.В. Иммунологические проблемы апоптоза. М., 2002.  [Baryshnikov A.Yu., Shishkin Yu.V. Immunologicheskiye problemy apoptoza (Immunological problems of apoptosis). , 2002.]
  36. Miyawaki T., Uehara T., Nibu R. et al. Differential expression of apoptosisrelated Fas antigen on lymphocyte subpopulations in human peripheral blood. J. Immunol. 1992; 149(11): 3753–8.
  37. Lechner H., Amort M., Steger M.M. et al. Regulation of CD95 (APO-1) expression and the induction of apoptosis in human T cells: changes in old age. Int. Arch. Allergy Immunol. 1996; 110(3): 238–43.
  38. Kotani T., Aratake Y., Kondo S. et al. Expression of functional Fas antigen on adult T-cell leukemia. Leuk. Res. 1994; 18(4): 305–10.