Abstract
WW domain binding protein 5 (WBP5), also known as Transcriptional Elongation Factor A like 9 (TCEAL9) has been proposed as a candidate oncogene for human colorectal cancers with microsatellite instability and as a predictive indicator of small cell lung cancers. Furthermore, several independent studies have proposed WBP5, and its association with Wilms Tumor-1 (WT1) expression, as part of a gene expression-based risk score for predicting survival and clinical outcome in patients with Acute Myeloid Leukaemia (AML). To date, the prognostic significance of the sole WBP5 expression and its impact on the survival outcome in AML patients remains largely understudied. In the present study, we have made use of publicly available patient expression arrays and have developed an unbiased approach to classify AML patients into low versus high WBP5 expressers and to balance them for known mutations and cytogenetic findings. Interestingly, we found that patients characterized by high WBP5 expression displayed inferior overall and event-free survival rates. Notably, gene expression profiling showed that patients with high WBP5 had elevated expression of several HOX cluster genes, such as HOXA5, HOXA7, HOXA9 and HOXA10, and several of their partner proteins, such as MEIS1 and FOXC1, which have been demonstrated to be causative for AML. Taken together, our data suggest that WBP5 expression level could serve as an indicator for prognosis and survival outcome in patients with AML.
Highlights
WW domain binding protein 5 (WBP5), known as Transcriptional Elongation Factor A like 9 (TCEAL9) has been proposed as a candidate oncogene for human colorectal cancers with microsatellite instability and as a predictive indicator of small cell lung cancers
Considering that NPM1c and FLT3-ITD, often found together, are indicators of bad prognosis while CEBPA and t(8;21) predict a more favourable outcome, we postulated that this observation could account for the inferior overall and event-free survival observed in the cohort of WBP5high patients
We looked at the expression of genes that have been shown to be directly involved in HOXA-driven leukemogenesis and observed a significant increase in the expression of GATA236, while no difference was observed for FLT39,37,38, MYB39,40 or CEBPA41
Summary
The overall survival (OS) and event-free survival (EFS) scores were determined using non-parametric Kaplan-Meyer estimates; comparison of survival between the low and high WBP5 subgroups was based on two-sided log rank test. Raw CEL data was downloaded for each patient and expression values were calculated, background corrected, log[2] transformed and quantile normalized in R (version 3.6.0) using affy package (version 1.62.0) and the rma function. Patients were shuffled in and out of the high and low expressing subgroups until there was no significant proportion of a specific cytogenetic abnormality, disease marker expression, age or gender. For the GSE6891, GSE1241721 and GSE3764229 datasets, the high expressing subgroup and the low expressing subgroup were compared for each probe using overall survival data. P-values represent Wilcoxon rank-sum test results comparing high and low expressing patients. Statistical analysis throughout this study was determined by performing t-test for pairwise comparison and the p-values are indicated where appropriate
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