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Ligation of the CD44 adhesion molecule reverses blockage of differentiation in human acute myeloid leukemia

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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Figure 1: AML classification by French-American-British criteria1.
Figure 2: H90 monoclonal antibody against CD44 induces differentiation of AML1/2 to AML5 blasts.
Figure 3: H90 induces differentiated cytological features in AML3 and AML5 blasts.
Figure 4: Mechanisms associated with CD44-induced differentiation of AML blasts.

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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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Correspondence to Florence Smadja-Joffe.

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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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