The ongoing conundrum of MLL-AF4 driven leukemogenesis.

endothelial cell and platelet b 3 integrins during thrombus formation in vivo, thereby regulating integrin activity. 5 Integrins are integral membrane proteins that mediate cell-cell adhesion and cell-matrix interactions. These molecules are essential for hematopoiesis, vascular development, immune and inflammatory responses, and hemostasis. Integrins are signaling receptors that can signal information bidirectionally across the plasma membrane. In circulating blood cells, integrins are normally in an active (resting) state with low affinity for their ligands. Upon activation, they can quickly change their conformation to an activated, high-affinity state, a process often referred to as inside-out signaling (see figure). 6 In the present study, Hahm et al demonstrate a new mechanism by which the adhesiveness of the b 2-integrin Mac-1 can be regulated under inflammatory conditions. The authors show that the specific deletion of PDI in myeloid cells abolishes neutrophil recruitment. By using blocking antibodies and knockout mice, they convincingly demonstrate that eliminating or blocking PDI reduces neutrophil adhesion and crawling by regulating Mac-1 adhesiveness. Although Mac-1 is also involved in neutrophil transmigration, 7 the authors have not investigated this important step in this study. In addition to this, the in vivo data in the present study show that exogenous PDI can also bind to the inflamed endothelium and may regulate the activation status of endothelial cells and the expression of endothelial junctional molecules, thereby affecting neutrophil recruitment. Therefore, the role of PDI in neutrophil transmigration has to be addressed in future studies. Other studies demonstrated that PDI interacts with a II b 3 and a v b 3 integrins on platelets and endothelial cells, respectively. 5,8 In biochemistry experiments, the authors nicely showed that PDI interacts with Mac-1 and that activated Mac-1 colocalizes with PDI in lipid rafts. 1 To directly prove the interaction of PDI and Mac-1, Hahm et al 1 performed surface plasmon resonance using recombinant proteins. The results showed that PDI can directly bind to Mac-1. However, as exogenous PDI still binds to a M b 2 integrin-deficient neutrophils, it is likely that the regulatory role of PDI in integrin function is not limited to Mac-1. Integrins contain several highly conserved cysteine residues. Some of the cysteines are disulfide-bonded and some exist as free thiols. Cleavage of disulfide bonds appears to be involved in the activation of integrins. The reducing agent dithiothreitol activates integrins on platelets and neutrophils by reduction of disulfide bonds within the integrin's cysteine-rich repeat. …