VEGFC Predicts Poor Outcome in Pediatric as Well as Adult Acute Myeloid Leukemia: Insights in Associated Gene Expression Profiles.

Abstract 997

Poster Board I-19

A high vascular endothelial growth factor-C (VEGFC) mRNA level of primary blasts of pediatric Acute Myeloid Leukemia (AML) patients correlates with increased in vitro drug resistance and slow AML blast disappearance during induction therapy in vivo; measured by higher blast counts on day 15 in the bone marrow and a prolonged interval towards complete remission (HJM de Jonge et al. Clinical Cancer Research 2008).

We set out to study both the effect of VEGFC on long term survival in AML and elucidate gene expression profiles associated with VEGFC expression by using Affymetrix HGU133Plus2.0 gene expression data of 100 pediatric and 525 adult AML patients.

Pediatric AML patients with a high VEGFC mRNA expression level (i.e. above the median VEGFC expression level) showed a significantly shortened overall survival (P = .041, hazard ratio = 1,81). Among the adult cohort of 525 AML samples, patients with a high VEGFC mRNA level also had significantly reduced overall survival and event free survival (OS and EFS) compared to patients with a low VEGFC level (P < .001, hazard ratio = 1,41 for OS and P = .002, hazard ratio = 1,44 for EFS). The continuous variable VEGFC maintained its prognostic significance for OS and EFS in a multivariate cox-regression model after correction for possible confounding effects of age, white blood cell count, cytogenetic risk group (i.e. favorable, intermediate and unfavorable), NPM1 mutation and FLT3-ITD (P = .031, odds ratio 1.37 for OS and P = .008, odds ratio 1.42 for EFS).

Differentially expressed probe sets were identified that distinguished patients with high from those with low VEGFC mRNA expression using a multivariate permutation test in Biometric Research Branch ArrayTools (BRB ArrayTools). Next, gene arrays of the pediatric AML cohort and a publicly available adult AML cohort of 180 gene arrays (Tomasson et al. Blood 2008) were used for validation of these probe sets. Finally, after two validation steps 569 probe sets were found to show differential high expression and 51 probe sets revealed differential low expression in AML with high mRNA levels of VEGFC, representative of distinctive biological processes (represented by GO-categories). Cell proliferation, VEGF receptor activity, signal transduction (e.g. PAK3 and SOS2 which are upstream activators of MEK1) and angiogenesis were upregulated, whereas genes associated with apoptosis (e.g. TIA1 and ANP32A) were found to be down regulated in AML with elevated VEGFC. In conclusion, high VEGFC mRNA expression levels are associated with reduced survival in adult and pediatric AML. Following the analysis of gene expression data in three independent AML cohorts the data suggest the involvement of specific biological processes in AML with (high) VEGFC expression with potential therapeutic impact.