Abstract
Blockage in myeloid differentiation characterizes acute myeloid leukemia (AML); the stage of the blockage defines distinct AML subtypes (AML1/2 to AML5). Differentiation therapy in AML has recently raised interest because the survival of AML3 patients has been greatly improved using the differentiating agent retinoic acid. However, this molecule is ineffective in other AML subtypes. The CD44 surface antigen, on leukemic blasts from most AML patients, is involved in myeloid differentiation. Here, we report that ligation of CD44 with specific anti-CD44 monoclonal antibodies or with hyaluronan, its natural ligand, can reverse myeloid differentiation blockage in AML1/2 to AML5 subtypes. The differentiation of AML blasts was evidenced by the ability to produce oxidative bursts, the expression of lineage antigens and cytological modifications, all specific to normal differentiated myeloid cells. These results indicate new possibilities for the development of CD44-targeted differentiation therapy in the AML1/2 to AML5 subtypes.
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References
Bennett, J.M., Catovsky, D. & Daniel, M.T. Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-British-American Cooperative Group. Ann. Intern. Med. 103, 620– 625 (1985).
Rowley, J.D., Golomb, H.M. & Dougherty, G.J. 15;17 translocation, a consistent chromosomal change in acute promyelocytic leukemia. Lancet 1, 549–550 (1977).
Bishop, J.F. et al. A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. Blood 87, 1710– 1717 (1996).
Degos, L.C. et al. All-trans-retinoic acid as a differentiating agent in the treatment of acute promyelocytic leukemia. Blood 85, 2643–2653 (1995).
Legras, S. et al. A strong expression of CD44-6v correlates with shorter survival patients with acute myeloid leukemia. Blood 91, 3401–3413 (1998).
Aruffo, A., Stamenkovic, I., Melnick, M., Underhill, C.B. & Seed, B. CD44 is the principal cell surface receptor for hyaluronate. Cell 61, 1303– 1313 (1990).
Miyake, K., Underhill, C.B., Lesley, J. & Kincade, P.W. Hyaluronate can function as a cell adhesion molecule and CD44 participates in hyaluronate recognition. J. Exp. Med. 172, 69–75 (1990).
Gunji, Y.H. et al. Expression and function of adhesion molecules on human hematopoietic stem cells: CD34+LFA-1- cells are more primitive than CD34+LFA-1+. Blood 80, 429–436 (1992).
Ghaffari, S., Dougherty, G.J., Lansdorp, P.M., Eaves, A.C. & Eaves, C.J. Differentiation-associated changes in CD44 isoform expressing ruding normal hematopoiesis and their alteration in chronic myeloid leukemia. Blood 86, 2976 –2985 (1995).
Koopman, G. et al. Triggering of the CD44 antigen on T lymphocytes promotes T cell adhesion through the LFA-1 pathway. J. Immunol. 145, 3589–3593 (1990).
Webb, D.S.A., Shimizu, Y., van Seventer, G.A., Shaw, S. & Gerrard, T.L. LFA-3, CD44 and CD45: physiologic triggers of human monocytes TNF and IL-1 release. Science 249, 1295–1297 (1990).
Ayroldi, E. et al. CD44 (Pgp-1) inhibits CD3 and dexamethasone-induced apoptosis. Blood 86, 2672–2678 (1995).
Galandrini, R., Galluzzo, E., Albi, N., Grossi, C.E. & Velardi, A. Hyaluronate is costimulatory for human T cell effector functions of human clones. J. Immunol. 153, 21–31 (1994).
Delfino, D.V. et al. Role of CD44 in the development of natural killer cells from precursors in long-term cultures of mouse bone marrow. J. Immunol. 152, 5171–5179 ( 1994).
Taher, E. et al. Signaling through CD44 is mediated by tyrosine kinases association with p56lck in T lymphocytes. J. Biol. Chem. 271, 2863–2867 (1996).
Trochon, V. et al. Evidence of involvement of CD44 in endothelial cell proliferation, migration and angiogenesis in vitro. Int. J. Cancer 66, 664–668 (1996).
Noble, P.W., Lake, F.R., Henson, P.M. & Riches, D.W.H. Hyaluronate activation of CD44 induces insulin-like growth factor-1 expression by a tumor necrosis factor-dependent mechanism in murine macrophages. J. Clin. Invest. 91, 2368–2377 ( 1993).
Noble, P.W., McKee, C.M. & Cowman, M. Hyaluronan fragments activate an NF-kB/I-kB autoregulary loop in murine macrophages. J. Exp. Med. 183, 2373–2378 (1996).
Mendelsohn, N., Gilbert, H., Christman, J. & Acs, G. Effects of maturation on the response of human promyelocytic leukemia cells (HL-60) to the tumor promoter 12-O-tetradecanoyl phorbol-13-acetate. Cancer. Res. 40, 1469–1474 ( 1980).
Goyert, S.M. et al. CD14 Workshop Panel Report in Leukocytes Typing VI (eds. Kishimoto, T. et al.) 963–965 (Garland Publishing, New York, 1997).
Kannagi R. CD15 Workshop Panel Report in Leukocytes Typing VI (eds. Kishimoto, T. et al.) 348–351 (Garland Publishing, New York, 1997).
Griffin, J.D. et al. Granulocyte-macrophage colony-stimulating factor and other cytokines regulate surface expression of the leukocyte adhesion molecule-1 on human neutrophiles, monocytes, and their precursors. J. Immunol. 145, 576–584 ( 1990).
Huet, S. et al. CD44 contributes to T cell activation: J. Immunol . 142, 798–801 ( 1989).
Denning, S. M., Le P. T., Singer, K.H. & Haynes, B.F. Antibodies against the CD44 p80, lymphocyte homing receptor molecule augment human peripheral blood T cell activation. J. Immunol. 144, 7–15 (1990).
Chomienne, C. et al. All-trans retioic acid in acute promyelocytic leukemias. II. In vitro studies: structure-function relationship. Blood 76, 1710–1717 ( 1990).
Slack, J.L. & Gallagher, R.E. The molecular biology of acute promyelocytic leukemia. Cancer Treat. Res. 99, 75–124 (1999).
Raelson, J.V. et al. The PML/RARα oncoprotein is a direct molecular target of retinoic acid in acute promyelocytic leukemia cells. Blood 88, 2826–2832 (1996).
Metcalf, D. Hematopoietic regulators. Trends Biol. Sci. 17, 286–290 (1992).
Morimoto, K. et al. CD44 mediates hyaluronan binding by human myeloid KG1a and KG1 cells. Blood 83, 657– 662 (1994).
Zhong, Z. et al. Monoclonal antibodies to CD44 and their influence on hyaluronan recognition. J. Cell Biol. 130, 485– 495 (1995).
Kincade, P.W., Zhong, Z., Katoh, S. & Hanson, L. The importance of the cellular environment to function of the CD44 matrix receptor. Curr. Opin. Cell Biol. 9, 635–642 (1997).
Ghaffari, S., Dougherty, G.J., Eaves, A.C. & Eaves, C.J. Altered patterns of CD44 epitope expression in human chronic and acute myeloid leukemia. Leukemia 10, 1773– 1781 (1996).
Delpech, B., Bertrand, P. & Maingonnat, C. Immunoenzymoassay of the hyaluronic acid-hyaluronectin interaction: application to the detection of hyaluronic acid in serum of normal subjects and cancer patients. Anal. Bioch. 149, 555–565 (1985).
Tenen. D.G., Hromas, R., Licht, J.D. & Zhang, D. Transcription factors, normal myeloid development, and leukemia. Blood 90, 489–519 (1997).
Terstappen, L.W.M.M. et al. Flow cytometric characterization of acute myeloid leukemia. Part I. Significance of light scattering properties. Leukemia 5, 315–320 (1991).
Delpech, B. et al. Interaction of hyaluronectin with hyaluronic acid oligosaccharides. J. Neurochem. 45, 434– 439 (1985).
Lesley, J., Hyman, R. & Kincade, P.W. CD44 and its interaction with the extracellular matrix. Adv. Immunol. 54, 271– 335 (1993).
Sambrouk, J., Fritch, E.F. & Maniatis, T. in Molecular Cloning. A Laboratory Manual. (ed. Nolan, C.) 700–787 (Cold Spring Laboratory Press, Cold Spring Harbor, New York, 1989).
Conover, W.J. in Practical Nonparametric Statistics 5, 213– 338 (J. Wiley and Sons, New York, 1980).
Acknowledgements
We thank P. Bertrand (Centre Henri Becquerel, Rouen, France) for preparing HA-12 oligosaccharides, F. Zassadowski (Hôpital St. Louis, Paris, France) for his technical assistance in AML3 studies and S. Chevret (Hôpital St. Louis, Paris, France) for statistical analysis. We are grateful to N. Smadja and M. Allouche for criticisms and suggestions on the manuscript, to V. Praloran (Centre Hospitalier, Limoges, France), and A. Charpentier (Hôpital P. Brousse, Villejuif, France) for supplying AML samples, and to N. Vriz and A. Talia for editorial assistance. This work was supported by Inserm, Association pour la Recherche Contre le Cancer, Ligue Nationale du Cancer and Association Nouvelles Recherches Biomédicales.
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Charrad, RS., Li, Y., Delpech, B. et al. Ligation of the CD44 adhesion molecule reverses blockage of differentiation in human acute myeloid leukemia. Nat Med 5, 669–676 (1999). https://doi.org/10.1038/9518
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DOI: https://doi.org/10.1038/9518
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