title: Combined PER2 and CRY1 expression predicts outcome in chronic lymphocytic leukemia.
abstract: The objective of this study was to confirm previous results regarding the differential expression and prognostic significance of the circadian gene CRY1 in chronic lymphocytic leukemia (CLL) patients and its relationship with the expression of other circadian genes and well-established prognostic markers. We also aimed to investigate whether the peripheral circadian machinery may be deregulated in CLL cells. The expression of CRY1, PER1, and PER2 was determined by real-time reverse transcriptase polymerase chain reaction (RT-PCR) in 116 CLL patients. The expression at sequential time points over a 24-h period was measured in six CLL patients and six normal donors. We confirmed the differential expression of CRY1 in ZAP-70(+)/CD38(+) and ZAP-70(-)/CD38(-) CLL samples. Subgroups formed according to CRY1 expression levels differed significantly in time to treatment. This difference was even more pronounced for subgroups stratified by a CRY1 : PER2 expression ratio and the ratio was an independent prognostic marker in a multivariate model. Furthermore, our data indicate disturbances in the periodic expression of circadian genes in CLL cells. Because of their role in the expression of cell cycle-related and DNA-damage response genes, we suggest that the deregulated expression of circadian genes may be linked to the molecular pathogenesis of CLL.
authors.affiliation: Department of Hematology, University Hospital, Hufelandstrasse 55, Essen, Germany. lewin.eisele@uni-due.de
authors.forename: Lewin
authors.initials: L
authors.lastname: Eisele
authors.forename: Robert
authors.initials: R
authors.lastname: Prinz
authors.forename: Ludger
authors.initials: L
authors.lastname: Klein-Hitpass
authors.forename: Holger
authors.initials: H
authors.lastname: Nückel
authors.forename: Kerstin
authors.initials: K
authors.lastname: Lowinski
authors.forename: Jürgen
authors.initials: J
authors.lastname: Thomale
authors.forename: Lars C
authors.initials: LC
authors.lastname: Moeller
authors.forename: Ulrich
authors.initials: U
authors.lastname: Dührsen
authors.forename: Jan
authors.initials: J
authors.lastname: Dürig
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D021081:Chronobiology Disorders / Q000235:genetics; D002940:Circadian Rhythm / Q000235:genetics; D056931:Cryptochromes; D004260:DNA Repair / Q000235:genetics; D005260:Female; D005420:Flavoproteins / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007700:Kinetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D056950:Period Circadian Proteins; D011237:Predictive Value of Tests; D011379:Prognosis; D014157:Transcription Factors / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: C538963:CRY1 protein, human; D056931:Cryptochromes; D005420:Flavoproteins; D009687:Nuclear Proteins; C421902:PER2 protein, human; D056950:Period Circadian Proteins; D014157:Transcription Factors