title: Epigenetic silencing of the circadian clock gene CRY1 is associated with an indolent clinical course in chronic lymphocytic leukemia.
abstract: Disruption of circadian rhythm is believed to play a critical role in cancer development. Cryptochrome 1 (CRY1) is a core component of the mammalian circadian clock and we have previously shown its deregulated expression in a subgroup of patients with chronic lymphocytic leukemia (CLL). Using real-time RT-PCR in a cohort of 76 CLL patients and 35 normal blood donors we now demonstrate that differential CRY1 mRNA expression in high-risk (HR) CD38+/immunoglobulin variable heavy chain gene (IgVH) unmutated patients as compared to low-risk (LR) CD38-/IgVH mutated patients can be attributed to down-modulation of CRY1 in LR CLL cases. Analysis of the DNA methylation profile of the CRY1 promoter in a subgroup of 57 patients revealed that CRY1 expression in LR CLL cells is silenced by aberrant promoter CpG island hypermethylation. The methylation pattern of the CRY1 promoter proved to have high prognostic impact in CLL where aberrant promoter methylation predicted a favourable outcome. CRY1 mRNA transcript levels did not change over time in the majority of patients where sequential samples were available for analysis. We also compared the CRY1 expression in CLL with other lymphoid malignancies and observed epigenetic silencing of CRY1 in a patient with B cell acute lymphoblastic leukemia (B-ALL).
authors.affiliation: Department of Hematology, University Hospital, Essen, Germany.
authors.forename: Maher
authors.initials: M
authors.lastname: Hanoun
authors.forename: Lewin
authors.initials: L
authors.lastname: Eisele
authors.forename: Masako
authors.initials: M
authors.lastname: Suzuki
authors.forename: John M
authors.initials: JM
authors.lastname: Greally
authors.forename: Andreas
authors.initials: A
authors.lastname: Hüttmann
authors.forename: Semra
authors.initials: S
authors.lastname: Aydin
authors.forename: René
authors.initials: R
authors.lastname: Scholtysik
authors.forename: Ludger
authors.initials: L
authors.lastname: Klein-Hitpass
authors.forename: Ulrich
authors.initials: U
authors.lastname: Dührsen
authors.forename: Jan
authors.initials: J
authors.lastname: Dürig
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D057906:Circadian Clocks / Q000235:genetics*; D018899:CpG Islands; D056931:Cryptochromes / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D020868:Gene Silencing; D050438:Genes, Immunoglobulin Heavy Chain; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic
chemical_list: C538963:CRY1 protein, human; D056931:Cryptochromes; D051997:ADP-ribosyl Cyclase 1