HIF1A mRNA overexpression found to be an independent prognostic indicator for CLL

This month in Leukemia Research, the first ever analysis of HIF1A mRNA expression as a prognostic indicator in CLL was published by Christos K. Kontos of the University General Hospital "Attikon", Athens, Greece, and colleagues.

Peripheral Blood Mononuclear Cells (PBMCs) were isolated from 33 non-leukemic blood donors as controls and 88 patients with CLL. Total RNA was extracted from these PBMCs and poly(A)-RNA was reversely transcribed. Real-time PCR was used to measure the amount of HIF1A mRNA.

Key Highlights:

• Patient characteristics (n = 88)
  • Gender: male = 62, female = 26
  • Median age at diagnosis = 70yrs (range, 50–90yrs)
  • Binet staging: stage A = 50 (56.8%); stage B = 16 (18.2%); stage C = 22 (25.0%)
  • CD38+ = 15 (17.0%)
  • Early apoptosis index of clonal B-cells = 55 samples, 0.01–54.8 (median, 47)
  • IGHV mutations = 45 cases (51.1%)
• HIF1A mRNA expression
  • Leukemic cells: 0.075–16.45 RQU, mean ± SE of 4.19 ± 0.55
  • Normal cells: 0.087–4.34 RQU, mean ± SE of 1.60 ± 0.20
  • HIF1A mRNA levels were not statistically different (P = 0.21)
• Prognostic value of HIF1A mRNA overexpression
  • Classification: 39 pts (44.3%) = HIF1A mRNA negative; 49 pts (55.7%) = HIF1A mRNA positive
  • Estimated median OS = 73 months (95% CI, 50–96 months)
  • OS significantly lower in HIF1A mRNA positive pts versus negative pts (P = 0.001)
  • Significant (P = 0.002) ~4-fold increased risk of death for HIF1A mRNA positive pts compared to negative pts
  • HIF1A overexpression is a significant prognostic indicator in CLL (P < 0.001); shown to be independent of CD38 expression, wild type IGHV, Binet/Rai stage, or risk group (P < 0.001 for all cases)
• HIF1A prognostic value in CLL subgroups
  • In intermediate- and high-risk pts: those overexpressing HIF1A mRNA had shorter OS than those with low HIF1A mRNA expression (P = 0.008 in both subgroups)
  • The presence of HIF1A mRNA expression predicted unfavorable outcomes in CLL pts whose disease was either CD38 positive or negative (P = 0.003 and 0.018, respectively)
  • Pts with wild-type IGHV and high HIF1A mRNA expression had significantly poorer OS probabilities than pts with wild-type IGHV and low HIF1A mRNA expression (P < 0.001)

The authors concluded that high HIF1A mRNA expression was associated with a poorer prognosis than patients with low HIF1A mRNA expression and so potentially represents a novel, prognostic biomarker. The authors went on to hypothesize that other surrogate prognostic markers could be combined with HIF1A mRNA expression to make up a multi-parametric prognostic index. The prognostic value of high HIF1A mRNA overexpression was found to be independent of other established prognostic indicators such as disease stage, IGHV mutational status, and CD38 expression.

Abstract:

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.