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PLoS One. 2013;8(4):e60823. doi: 10.1371/journal.pone.0060823. Epub 2013 Apr 1.

Leukemia Mediated Endothelial Cell Activation Modulates Leukemia Cell Susceptibility to Chemotherapy through a Positive Feedback Loop Mechanism.

Author information

1
Department of Biological Sciences, Oakland University, Rochester, Michigan, USA.

Abstract

In acute myeloid leukemia (AML), the chances of achieving disease-free survival are low. Studies have demonstrated a supportive role of endothelial cells (ECs) in normal hematopoiesis. Here we show that similar intercellular relationships exist in leukemia. We demonstrate that leukemia cells themselves initiate these interactions by directly modulating the behavior of resting ECs through the induction of EC activation. In this inflammatory state, activated ECs induce the adhesion of a sub-set of leukemia cells through the cell adhesion molecule E-selectin. These adherent leukemia cells are sequestered in a quiescent state and are unaffected by chemotherapy. The ability of adherent cells to later detach and again become proliferative following exposure to chemotherapy suggests a role of this process in relapse. Interestingly, differing leukemia subtypes modulate this process to varying degrees, which may explain the varied response of AML patients to chemotherapy and relapse rates. Finally, because leukemia cells themselves induce EC activation, we postulate a positive-feedback loop in leukemia that exists to support the growth and relapse of the disease. Together, the data defines a new mechanism describing how ECs and leukemia cells interact during leukemogenesis, which could be used to develop novel treatments for those with AML.

PMID:
23560111
PMCID:
PMC3613371
DOI:
10.1371/journal.pone.0060823
[Indexed for MEDLINE]
Free PMC Article

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