Histone deacetylase inhibitors potently repress CXCR4 chemokine receptor expression and function in acute lymphoblastic leukaemia
Roman Crazzolara
Tyrolean Cancer Research Institute (TCRI) at the University of Innsbruck,
Department of Paediatrics, Innsbruck University Hospital, Innsbruck, Austria,
Search for more papers by this authorKarin Jöhrer
Tyrolean Cancer Research Institute (TCRI) at the University of Innsbruck,
Search for more papers by this authorRicky W. Johnstone
Gene Regulation Laboratory, Peter MacCallum Cancer Institute, Melbourne, Australia,
Search for more papers by this authorRichard Greil
Tyrolean Cancer Research Institute (TCRI) at the University of Innsbruck,
Laboratory of Molecular Cytology, Department of Internal Medicine, Innsbruck University Hospital, and
Search for more papers by this authorReinhard K Ofler
Tyrolean Cancer Research Institute (TCRI) at the University of Innsbruck,
Division of Molecular Pathophysiology, Institute of Pathophysiology, University of Innsbruck, Innsbruck, Austria
Search for more papers by this authorBernhard Meister
Tyrolean Cancer Research Institute (TCRI) at the University of Innsbruck,
Department of Paediatrics, Innsbruck University Hospital, Innsbruck, Austria,
Search for more papers by this authorDavid Bernhard
Tyrolean Cancer Research Institute (TCRI) at the University of Innsbruck,
Division of Molecular Pathophysiology, Institute of Pathophysiology, University of Innsbruck, Innsbruck, Austria
Search for more papers by this authorRoman Crazzolara
Tyrolean Cancer Research Institute (TCRI) at the University of Innsbruck,
Department of Paediatrics, Innsbruck University Hospital, Innsbruck, Austria,
Search for more papers by this authorKarin Jöhrer
Tyrolean Cancer Research Institute (TCRI) at the University of Innsbruck,
Search for more papers by this authorRicky W. Johnstone
Gene Regulation Laboratory, Peter MacCallum Cancer Institute, Melbourne, Australia,
Search for more papers by this authorRichard Greil
Tyrolean Cancer Research Institute (TCRI) at the University of Innsbruck,
Laboratory of Molecular Cytology, Department of Internal Medicine, Innsbruck University Hospital, and
Search for more papers by this authorReinhard K Ofler
Tyrolean Cancer Research Institute (TCRI) at the University of Innsbruck,
Division of Molecular Pathophysiology, Institute of Pathophysiology, University of Innsbruck, Innsbruck, Austria
Search for more papers by this authorBernhard Meister
Tyrolean Cancer Research Institute (TCRI) at the University of Innsbruck,
Department of Paediatrics, Innsbruck University Hospital, Innsbruck, Austria,
Search for more papers by this authorDavid Bernhard
Tyrolean Cancer Research Institute (TCRI) at the University of Innsbruck,
Division of Molecular Pathophysiology, Institute of Pathophysiology, University of Innsbruck, Innsbruck, Austria
Search for more papers by this authorAbstract
Summary. The chemokine receptor CXCR4 plays a crucial role in the survival and trafficking of leukaemia cells and requires further attention as human immunodeficiency virus type I (HIV-I) utilises CXCR4 as the major coreceptor for cellular entry. We demonstrated that inhibitors of histone deacetylases, currently being tested in clinical trials for the treatment of various tumours, extensively downregulated CXCR4 protein and mRNA levels in leukaemia cell lines and lymphoblasts from patients with childhood acute leukaemia. As a result, the ability of stromal cell-derived factor-1 to induce cellular migration was impaired. Repression of CXCR4 transcription by inhibitors of histone deacetylases might therefore represent a promising novel approach in the treatment of acute leukaemias.
References
- Bernhard, D., Ausserlechner, M.J., Tonko, M., Loffler, M., Hartmann, B.L., Csordas, A. & Kofler, R. (1999a) Apoptosis induced by the histone deacetylase inhibitor sodium butyrate in human leukemic lymphoblasts. FASEB Journal, 13, 1991–2001.
- Bernhard, D., Loffler, M., Hartmann, B.L., Yoshida, M., Kofler, R. & Csordas, A. (1999b) Interaction between dexamethasone and butyrate in apoptosis induction: non-additive in thymocytes and synergistic in a T cell-derived leukemia cell line. Cell Death and Differentiation, 6, 609–617.
- Bernhard, D., Skvortsov, S., Tinhofer, I., Hubl, H., Greil, R., Csordas, A. & Kofler, R. (2001) Inhibition of histone deacetylase activity enhances Fas receptor-mediated apoptosis in leukemic lymphoblasts. Cell Death and Differentiation, 8, 1014–1021.
- Bleul, C.C., Farzan, M., Choe, H., Parolin, C., Clark-Lewis, I., Sodroski, J. & Springer, T.A. (1996) The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry. Nature, 382, 829–833.
- Bradstock, K.F., Makrynikola, V., Bianchi, A., Shen, W., Hewson, J. & Gottlieb, D.J. (2000) Effects of the chemokine stromal cell-derived factor-1 on the migration and localization of precursor-B acute lymphoblastic leukemia cells within bone marrow stromal layers. Leukemia, 14, 882–888.
- Bresnick, E.H., John, S., Berard, D.S., LeFebvre, P. & Hager, G.L. (1990) Glucocorticoid receptor-dependent disruption of a specific nucleosome on the mouse mammary tumor virus promoter is prevented by sodium butyrate. Proceedings of the National Academy of Sciences of the United States of America, 87, 3977–3981.
- Burger, J.A., Burger, M. & Kipps, T.J. (1999) Chronic lymphocytic leukemia B cells express functional CXCR4 chemokine receptors that mediate spontaneous migration beneath bone marrow stromal cells. Blood, 94, 3658–3667.
- Crazzolara, R., Kreczy, A., Mann, G., Heitger, A., Eibl, G., Fink, F.M., Möhle, R. & Meister, B. (2001) High expression of the chemokine receptor CXCR4 predicts extramedullary organ infiltration in childhood acute lymphoblastic leukaemia (ALL). British Journal of Haematology, 115, 545–553.
- Jordan, N.J., Kolios, G., Abbot, S.E., Sinai, M.A., Thompson, D.A., Petraki, K. & Westwick, J. (1999) Expression of functional CXCR4 chemokine receptors on human colonic epithelial cells. Journal of Clinical Investigation, 104, 1061–1069.
- Ma, Q., Jones, D., Borghesani, P.R., Segal, R.A., Nagasawa, T., Kishimoto, T., Bronson, R.T. & Springer, T.A. (1998) Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. Proceedings of the National Academy of Sciences of the United States of America, 95, 9448–9453.
- Mariadason, J.M., Corner, G.A. & Augenlicht, L.H. (2000) Genetic reprogramming in pathways of colonic cell maturation induced by short chain fatty acids: comparison with trichostatin A, sulindac, and curcumin and implications for chemoprevention of colon cancer. Cancer Research, 60, 4561–4572.
- Mohle, R., Schittenhelm, M., Failenschmid, C., Bautz, F., Kratz-Albers, K., Serve, H., Brugger, W. & Kanz, L. (2000) Functional response of leukaemic blasts to stromal cell-derived factor-1 correlates with preferential expression of the chemokine receptor CXCR4 in acute myelomonocytic and lymphoblastic leukaemia. British Journal of Haematology, 110, 563–572.
- Muller, A., Homey, B., Soto, H., Ge, N., Catron, D., Buchanan, M.E., McClanahan, T., Murphy, E., Yuan, W., Wagner, S.N., Barrera, J.L., Mohar, A., Verastegui, E. & Zlotnik, A. (2001) Involvement of chemokine receptors in breast carcinoma metastasis. Nature, 410, 50–56.
- Nagasawa, T., Hirota, S., Tachibana, K., Takakura, N., Nishikawa, S., Kitamura, Y., Yoshida, N., Kikutani, H. & Kishimoto, T. (1996) Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature, 382, 635–638.
- Nishii, K., Katayama, N., Miwa, H., Shikami, M., Masuya, M., Shiku, H. & Kita, K. (1999) Survival of human leukaemic B-cell precursors is supported by stromal cells and cytokines: association with the expression of bcl-2 protein. British Journal of Haematology, 105, 701–710.
- Oberlin, E., Amara, A., Bachelerie, F., Bessia, C., Virelizier, J.L., Arenzana-Seisdedos, F., Schwartz, O., Heard, J.M., Clark-Lewis, I., Legler, D.F., Loetscher, M., Baggiolini, M. & Moser, B. (1996) The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature, 382, 833–835.
- Ruefli, A.A., Ausserlechner, M.J., Bernhard, D., Sutton, V.R., Tainton, K.M., Kofler, R., Smyth, M.J. & Johnstone, R.W. (2001) The histone deacetylase inhibitor and chemotherapeutic agent suberoylanilide hydroxamic acid (SAHA) induces a cell-death pathway characterized by cleavage of Bid and production of reactive oxygen species. Proceedings of the National Academy of Sciences of the United States of America, 98, 10833–10838.