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Leptomeningeal metastases are a serious neurological complication in cancer patients and associated with a dismal prognosis. Tumor cells that enter the subarachnoid space adhere to the leptomeninges and form tumor deposits. It is largely unknown which adhesion molecules mediate tumor cell adhesion to leptomeninges. We studied the role of integrin expression and activation in the progression of leptomeningeal metastases. For this study, we used a mouse acute lymphocytic leukemic cell line that was grown in suspension (L1210-S cell line) to develop an adherent L1210 cell line (L1210-A) by selectively culturing the few adherent cells in the cell culture. beta1, beta2, and beta3 integrins were in a constitutively high active state on L1210-A cells and in a low, but inducible, active state on L1210-S cells. Expression levels of these integrins were comparable in the two cell lines. Static adhesion levels of L1210-A cells on a leptomeningeal cell layer were significantly higher than those of L1210-S cells. All mice that were injected intrathecally with L1210-A cells died rapidly of leptomeningeal leukemia. In contrast, 45% long-term survival was seen after intrathecal injection of mice with L1210-S cells. Our data indicate that constitutive integrin activation on leukemic cells promotes progression of leptomeningeal leukemia by increased tumor cell adhesion to the leptomeninges. We argue that an aberrantly regulated inside-out signaling pathway underlies constitutive integrin activation on the adherent leukemic cell population.