Micrornas as therapeutic targets

Acute myeloid leukemia (AML) cells are dependent on integrins and chemokine receptors for migration and marrow homing. Moreover, adhesion within the marrow microenvironment results in chemotherapy resistance for AML as well as other hematologic malignancies, by activating survival pathways or interfering with apoptosis. Retention within the marrow is dependent on chemokine receptor type 4 (CXCR4), which mediates migration toward stromal derived factor (SDF)- 1, also known as CXCL12, whereas attachment is largely attributed to very late antigen (VLA)-4, an integrin that binds to both alternatively spliced fibronectin, a component of the extracellular matrix, and vascular cell adhesion molecule-1 (VCAM-1) on marrow stromal cells. There are correlations of the level of expression of both these receptors with outcomes in AML after treatment. Disruption of these two types of interactions can enhance chemotherapy-mediated cytotoxicity in laboratory studies. The anti-VLA-4 antibody, natalizumab, was approved for treatment of multiple sclerosis and Crohn’s disease several years ago, and this antibody or similar inhibitors of these types of interactions have now been included in clinical trials for different types of cancer. In the future, small molecule inhibitors or antibodies that interfere with adhesion proteins may become critical additions to standard chemotherapy approaches in AML.