mRNA overexpression of the hypoxia inducible factor 1 alpha subunit gene (HIF1A): An independent predictor of poor overall survival in chronic lymphocytic leukemia

- A cost-effective qPCR method for quantification of HIF1A mRNA levels was developed.
- HIF1A mRNA levels do not differ between normal blood samples and leukemic B cells.
- High HIF1A mRNA expression predicts poor overall survival in CLL patients.
- Prognostic significance of HIF1A mRNA is independent of clinicopathological factors.
- HIF1A mRNA is an unfavorable prognosticator in distinct subgroups of CLL patients.

The hypoxia inducible factor 1 (HIF1) is a heterodimeric transcription factor that ultimately regulates cellular responses to changes in oxygen tension. In this study, we examined the potential diagnostic and prognostic potential of the mRNA expression of HIF1 regulatory α-subunit (HIF1A) in chronic lymphocytic leukemia (CLL). For this purpose, total RNA was isolated from peripheral blood mononuclear cells collected from 88 CLL patients and 33 non-leukemic blood donors, and poly(A)-RNA was reversely transcribed. HIF1A mRNA levels were quantified using real-time PCR. Kaplan-Meier survival analysis showed that high HIF1A mRNA expression predicts inferior overall survival for CLL patients (p = 0.001). Bootstrap univariate Cox regression analysis confirmed that HIF1A mRNA overexpression is a significant unfavorable prognosticator in CLL (hazard ratio = 3.75, bias-corrected and accelerated 95% confidence interval = 1.43-24.36, bootstrap p < 0.001), independent of other established prognostic factors, including CD38 expression, the mutational status of the immunoglobulin heavy chain variable region (IGHV), and the clinical stage (Binet or Rai stage) or risk group (p < 0.001 in all cases). Interestingly, HIF1A mRNA positivity retains its unfavorable prognostic value in distinct subgroups of patients, stratified according to established prognostic factors. Thus, HIF1A mRNA overexpression can be regarded as a promising, independent molecular biomarker of unfavorable prognosis in CLL.