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Up-regulation of VEGF and its receptor in refractory leukemia cells.

OBJECTIVE
To analyze the causative mechanisms in refractory leukemia cells.


METHODS
Vascular endothelial growth factor (VEGF) blood plasma concentrations in 35 de novo, 6 relapse, 20 remission leukemia patients and 10 healthy kids were determined via ELISA analyses. Transcription levels of the VEGF receptors (VEGFR) Fms-like tyrosine kinase-1 (Flt-1) and kinase-domain insert containing receptor (KDR) were determined in participants' leucocytes with RT-PCR. Apoptosis rates as well as Cyt-C and Caspase-3 expression was determined in Jurkat, Jurkat(Bcl-2), healthy and recurrent leukemia leukocytes with and without VP-16 applications via flow cytometry. Total Akt (t-Akt) expression and its phosphorylation (p-AKT) status in leukocytes of the participants were analyzed with western blots.


RESULTS
Healthy children and the remission group had the lowest blood plasma VEGF concentrations (91.16±41.34 vs. 135.80±111.28 pg/ml), followed by de novo leukemia patients (362.49±195.68 pg/ml-494.19±186.23 pg/ml) and relapse patients (574.37±278.45 pg/ml) (P<0.01). The same trend was statistically significant visible for Flt-1 and KDR expressions in leukocytes of the participants. Stable Bcl-2 overexpression led to reduced apoptosis rates as well as Cyt-C and Caspase-3 expressions in Jurkat cells after VP-16 application, which was similar in leucocytes of remission patients. In contrast to no phosphorylation in healthy children, Akt was phosphorylated in 10% remission samples, 30% de novo leukemia samples and in 67% of recurrent leukemia leucocytes.


CONCLUSION
High VEGF plus VEGFR expression and AKT phosphorylation are highest in leukocytes of remission patients, suggesting VEGF signaling as a cause of reduced apoptosis susceptibility upon treatments.