The Possible Importance of ß3 Integrins for Leukemogenesis and Chemoresistance in Acute Myeloid Leukemia.

ABSTRACT

Acute myeloid leukemia (AML) is an aggressive bone marrow malignancy where the immature leukemia cells communicate with neighboring cells through constitutive cytokine release and through their cell surface adhesion molecules. The primary AML cells express various integrins. These heterodimeric molecules containing an α and a ß chain are cell surface molecules that bind extracellular matrix molecules, cell surface molecules and soluble mediators. The ß3 integrin (ITGB3) chain can form heterodimers only with the two α chains αIIb and αV. These integrins are among the most promiscuous and bind to a large number of ligands, including extracellular matrix molecules, cell surface molecules and soluble mediators. Recent studies suggest that the two ß3 integrins are important for leukemogenesis and chemosensitivity in human AML. Firstly, αIIb and ß3 are both important for adhesion of AML cells to vitronectin and fibronectin. Secondly, ß3 is important for the development of murine AML and also for the homing and maintenance of the proliferation for xenografted primary human AML cells, and for maintaining a stem cell transcriptional program. These last effects seem to be mediated through Syk kinase. The ß3 expression seems to be regulated by HomeboxA9 (HoxA9) and HoxA10, and the increased ß3 expression then activates spleen tyrosine kinase (Syk) and thereby contributes to cytokine hypersensitivity and activation of ß2 integrins. Finally, high integrin αV/ß3 expression is associated with an adverse prognosis in AML and decreased sensitivity to the kinase inhibitor sorafenib; this integrin can also be essential for osteopontin-induced sorafenib resistance in AML. In the present article, we review the experimental and clinical evidence for a role of ß3 integrins for leukemogenesis and chemosensitivity in AML.