Central nervous system involvement in acute lymphoblastic leukemia is mediated by vascular endothelial growth factor
Treatment of the central nervous system in acute lymphoblastic leukemia is critical, even in the absence of detectable involvement at diagnosis. This suggests subclinical involvement in many ALL patients at diagnosis. Multiple factors have been evaluated in relation to CNS involvement, which is described as leptomeningeal disease. This study identified vascular endothelial growth factor A (VEGF) as a mediator of CNS involvement of ALL.
The study used the immunodeficient NOD/SCID mouse model to investigate key molecular features of CNS disease in ALL, as a model to study leukemia-cell entry into the CNS. Patient ALL cells were successfully transplanted into these mice, and hematopoietic stem cell and meningeal cell suspensions were evaluated after autopsy. An in vivo component of the study saw mice assigned to receive bevacizumab, an inhibitor of VEGF, or placebo.
Overt leukemia was seen in all transplanted mice, and 9 of 15 developed CNS symptoms. The CNS+ phenotype was maintained with subsequent transplantations, indicating that CNS involvement is intrinsic to the ALL cell. CNS+ ALL was identified as having increased expression of VEGF, which regulates vascular permeability and transendothelial migration in addition to angiogenesis. The overall growth and proliferation of the ALL cells was not affected by VEGF capture in vitro by bevacizumab, but transendothelial ALL cell migration was decreased. This was replicated in vivo, with a clear reduction in CNS leukemia seen in the bevacizumab treated mice, although no reduction in their leukemia was observed.
While 9 mice developed CNS leukemia, this did not correspond to the patients from whom the xenografts were derived. As such, it is difficult to extrapolate completely from the mouse model to the human disease.