The effect of anti-CD44 monoclonal antibodies on differentiation and proliferation of human acute myeloid leukemia cells.

Acute myeloid leukemia (AML) is a clonal malignant disease characterized by an increasing number of immature myeloid cells arrested at various stages of granulocytic and monocytic differentiation. The stage of the blockage defines distinct AML subtypes (AML1 to AML5 are the most frequent ones). There is increasing evidence that the malignant clone is maintained by rare AML stem cells endowed with self-renewal capacity, which through extensive proliferation coupled to partial differentiation, generate leukemic progenitors and blasts, of which the vast majority have limited proliferative capacity. Contrarily to chemotherapy alone, which is still unable to cure most AML patients, the differentiation therapy, which consists in releasing the differentiation blockage of leukemic blasts, has succeeded, when it is combined with chemotherapy, to greatly improve the survival of AML3 patients, using retinoic acid as differentiating agent. However, this molecule is ineffective in other AML subtypes, which are the most frequent. We have shown that specific monoclonal antibodies (mAbs, H90 and A3D8) directed to the CD44 cell surface antigen, that is strongly expressed on human AML blasts, are capable of triggering terminal differentiation of leukemic blasts in AML1 to AML5 subtypes. These results have raised the perspective of developing a CD44-targeted differentiation therapy in most AML cases. Interestingly, these anti-CD44 mAbs can also induce the differentiation of AML cell lines, inhibit their proliferation and, in some cases, induce their apoptotic death. These results suggest that H90 and/or A3D8 mAbs may be capable to inhibit the proliferation of leukemic progenitors, to promote the differentiation of the leukemic stem cells at the expense of their self-renewal, and, perhaps, to induce their apoptotic death, thereby contributing to decrease the size of the leukemic clone. The challenges of an anti-CD44 based differentiation therapy in AML, and its importance in relation to the new other therapies developed in this malignancy, are discussed in this review.