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Central nervous system involvement in acute lymphoblastic leukemia is mediated by vascular endothelial growth factor

Vera Münch, Luca Trentin, Julia Herzig, Salih Demir, Felix Seyfried, Johann M. Kraus, Hans A. Kestler, Rolf Köhler, Thomas F. E. Barth, Geertruy te Kronnie, Klaus-Michael Debatin and Lüder H. Meyer

Key Points

  • Xenografted ALL cells faithfully recapitulate CNS leukemia and are characterized by high expression of VEGF, mediating CNS entry of ALL cells.

  • VEGF captured by bevacizumab in vivo specifically reduces CNS leukemia, providing a novel strategy to target CNS involvement in ALL.

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.

Abstract

In acute lymphoblastic leukemia (ALL), central nervous system (CNS) involvement is a major clinical concern. Despite nondetectable CNS leukemia in many cases, prophylactic CNS-directed conventional intrathecal chemotherapy is required for relapse-free survival, indicating subclinical CNS manifestation in most patients. However, CNS-directed therapy is associated with long-term sequelae, including neurocognitive deficits and secondary neoplasms. Therefore, molecular mechanisms and pathways mediating leukemia-cell entry into the CNS need to be understood to identify targets for prophylactic and therapeutic interventions and develop alternative CNS-directed treatment strategies. In this study, we analyzed leukemia-cell entry into the CNS using a primograft ALL mouse model. We found that primary ALL cells transplanted onto nonobese diabetic/severe combined immunodeficiency mice faithfully recapitulated clinical and pathological features of meningeal infiltration seen in patients with ALL. ALL cells that had entered the CNS and were infiltrating the meninges were characterized by high expression of vascular endothelial growth factor A (VEGF). Although cellular viability, growth, proliferation, and survival of ALL cells were found to be independent of VEGF, transendothelial migration through CNS microvascular endothelial cells was regulated by VEGF. The importance of VEGF produced by ALL cells in mediating leukemia-cell entry into the CNS and leptomeningeal infiltration was further demonstrated by specific reduction of CNS leukemia on in vivo VEGF capture by the anti-VEGF antibody bevacizumab. Thus, we identified a mechanism of ALL-cell entry into the CNS, which by targeting VEGF signaling may serve as a novel strategy to control CNS leukemia in patients, replacing conventional CNS-toxic treatment.

  • Submitted March 3, 2017.
  • Accepted May 21, 2017.
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