CD44 et hematopoiese

CD44 is a cell surface glycoprotein which displays several isoforms: a standard one (CD44s), and many variant isoforms (CD44v), generated by alternative splicing of variant exons. The standard CD44 isoform, which is the most common one, is expressed on all types of hematopoietic cells, and its level is particularly high on hematopoietic progenitor cells (CD34⁺ HPC), monocytic cells and activated lymphocytes. CD44 is thought to play an important role in the initial phases of hematopoiesis because blocking anti- CD44 monoclonal antibodies fully inhibit in vitro long term hematopoiesis on pre-established stroma. CD44, particularly the CD44-6v variant isoform, also has a crucial role in the function of lymphocytes. CD44 has been shown to be the principal cell surface receptor for hyaluronic acid (HA), a major glycosaminoglycan component of the extracellular matrix. However, its affinity for HA is not constitutive and a very important feature of CD44 displayed by CD34⁺ HPC, is its capacity to be rapidly activated by cytokines (Stem cell factor, IL-3, Granulo-monocytic-colony stimulating factor) which also stimulate the proliferation of HPC, via an 'inside-outside' mechanism which remains to be elucidated. Theses features shed the light on striking similarities in the functional regulation of CD44 and of the two integrin receptors VLA-4 and VLA-5, which are also expressed on HPC, and strongly suggest that cytokines may not only control the proliferation and the differentiation of HPC but also the adhesive' interactions between HPC and the bone marrow stroma. It has been shown that a significant number of human malignant hemopathies express increased levels of CD44 variant isoforms than their normal cellular counterpart. For example, CD44-6v isoforms are upregulated in non-Hodgkin's lymphoma (NHL) and acute myeloid leukemia (AML), CD44-9v and CD44-10v expression are increased myeloma and chronic myeloid leukemia, respectively. Moreover, the expression of variant isoforms correlates with an unfavorable clinical evolution in NHL, AML and myeloma, suggesting their possible role in these hematopoietic malignancies.