title: mRNA overexpression of the hypoxia inducible factor 1 alpha subunit gene (HIF1A): An independent predictor of poor overall survival in chronic lymphocytic leukemia.
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.
authors.affiliation: Second Department of Internal Medicine and Research Unit, University General Hospital "Attikon", 1 Rimini St., Haidari, 12462 Athens, Greece; Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Panepistimiopolis, 15701 Athens, Greece.
authors.forename: Christos K
authors.initials: CK
authors.lastname: Kontos
authors.affiliation: Second Department of Internal Medicine and Research Unit, University General Hospital "Attikon", 1 Rimini St., Haidari, 12462 Athens, Greece.
authors.forename: Sotirios G
authors.initials: SG
authors.lastname: Papageorgiou
authors.affiliation: Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Panepistimiopolis, 15701 Athens, Greece.
authors.forename: Marios A
authors.initials: MA
authors.lastname: Diamantopoulos
authors.affiliation: Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Panepistimiopolis, 15701 Athens, Greece.
authors.forename: Andreas
authors.initials: A
authors.lastname: Scorilas
authors.affiliation: Second Department of Internal Medicine and Research Unit, University General Hospital "Attikon", 1 Rimini St., Haidari, 12462 Athens, Greece.
authors.forename: Efthimia
authors.initials: E
authors.lastname: Bazani
authors.affiliation: Second Department of Internal Medicine and Research Unit, University General Hospital "Attikon", 1 Rimini St., Haidari, 12462 Athens, Greece.
authors.forename: Diamantina
authors.initials: D
authors.lastname: Vasilatou
authors.affiliation: Second Department of Internal Medicine and Research Unit, University General Hospital "Attikon", 1 Rimini St., Haidari, 12462 Athens, Greece.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Gkontopoulos
authors.affiliation: Second Department of Internal Medicine and Research Unit, University General Hospital "Attikon", 1 Rimini St., Haidari, 12462 Athens, Greece.
authors.forename: Eirini
authors.initials: E
authors.lastname: Glezou
authors.affiliation: Second Department of Internal Medicine and Research Unit, University General Hospital "Attikon", 1 Rimini St., Haidari, 12462 Athens, Greece.
authors.forename: Georgia
authors.initials: G
authors.lastname: Stavroulaki
authors.affiliation: Second Department of Internal Medicine and Research Unit, University General Hospital "Attikon", 1 Rimini St., Haidari, 12462 Athens, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Dimitriadis
authors.affiliation: Second Department of Internal Medicine and Research Unit, University General Hospital "Attikon", 1 Rimini St., Haidari, 12462 Athens, Greece. Electronic address: vas_pappa@yahoo.com.
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Pappa
mesh_terms: D014408:Biomarkers, Tumor / Q000097:blood; D016022:Case-Control Studies; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis* / Q000401:mortality; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger
keywords: CLL; Hematological malignancy; Prognostic biomarker; Real-time PCR; Tumor marker; Unfavorable prognosis