Essential roles of VLA-4 in the hematopoietic system

Abstract

Integrins are one of the major families of adhesion molecules and make various kinds of biological effects by mediating cell-cell and cell-matrix interactions. Among integrins, VLA-4 is expressed on many types of hematopoietic cells including stem/progenitor cells and it is considered as a critical regulator of adult hematopoiesis. Recent studies revealed that VLA-4 is not necessarily required for the development or maintenance of adult hematopoietic cells. On the other hand, it was proved that VLA-4 is essential for homeostasis of distribution of hematopoietic stem/progenitor cells (HSPCs) and mature lymphocytes in the body. The dynamic regulation of VLA-4 function is mediated by its conformational change, which is strictly linked to the interaction between alpha and beta cytoplasmic domains. The study using knockin mice showed that GFFKR sequence, a well-preserved motif in the alpha cytoplasmic domain of VLA-4, is critical for binding of alpha and beta cytoplasmic domains as well as regulation of hematopoietic cell distribution. Small molecules targeting this cytoplasmic interaction or ligand-VLA-4 interaction may become good candidates of new drugs for mobilization of hematopoietic stem cells. Several studies have suggested the impact of VLA-4 on chemotherapy sensitivity and prognosis in hematological malignancies, which awaits further investigations.