It has been postulated that inactivated beta1-integrins are involved in the disordered growth of hematopoietic tumor cells. We recently found that TNIIIA2, a peptide derived from tenascin-C, strongly activates beta1-integrins through binding with syndecan-4. We show here that Ramos Burkitt's lymphoma cells can survive and grow in suspension but undergo apoptosis when kept adhering to fibronectin by stimulation with TNIIIA2. Other integrin activators, Mg(2+) and TS2/16 (an integrin-activating antibody), were also capable of inducing apoptosis. The inactivation of ERK1/2 and Akt and the subsequent activation of Bad were involved in the apoptosis. The results using other hematopoietic tumor cell lines expressing different levels of fibronectin receptors (VLA-4 and VLA-5) showed that potentiated and sustained adhesion to fibronectin via VLA-4 causally induces apoptosis also in various types of hematopoietic tumor cells in addition to Ramos cells. Because TNIIIA2 requires syndecan-4 as a membrane receptor for activation of beta1-integrins, it induced apoptosis preferentially in hematopoietic tumor cells, which expressed both VLA-4 and syndecan-4 as membrane receptors mediating the effects of fibronectin and TNIIIA2, respectively. Therefore, normal peripheral blood cells, such as neutrophils, monocytes, and lymphocytes, which poorly expressed syndecan-4, were almost insusceptible to TNIIIA2-induced apoptosis. The TNIIIA2-related matricryptic site of TN-C could contribute, once exposed, to preventing prolonged survival of hematopoietic malignant progenitors through potentiated and sustained activation of VLA-4.