Epigenetic silencing of the circadian clock gene CRY1 is associated with an indolent clinical course in chronic lymphocytic leukemia

Maher Hanoun, Lewin Eisele, Masako Suzuki, John M. Greally, Andreas Hüttmann, Semra Aydin, René Scholtysik, Ludger Klein-Hitpass, Ulrich Dührsen, Jan Dürig

Research output: Contribution to journalArticle

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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).

Original languageEnglish (US)
Article numbere34347
JournalPLoS One
Volume7
Issue number3
DOIs
StatePublished - Mar 28 2012

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Cryptochromes
lymphocytic leukemia
Circadian Clocks
B-Cell Chronic Lymphocytic Leukemia
disease course
Epigenomics
epigenetics
circadian rhythm
Clocks
Genes
genes
promoter regions
Immunoglobulin Heavy Chain Genes
Methylation
methylation
immunoglobulins
Immunoglobulins
cryptochromes
Messenger RNA
CpG Islands

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Epigenetic silencing of the circadian clock gene CRY1 is associated with an indolent clinical course in chronic lymphocytic leukemia. / Hanoun, Maher; Eisele, Lewin; Suzuki, Masako; Greally, John M.; Hüttmann, Andreas; Aydin, Semra; Scholtysik, René; Klein-Hitpass, Ludger; Dührsen, Ulrich; Dürig, Jan.

In: PLoS One, Vol. 7, No. 3, e34347, 28.03.2012.

Research output: Contribution to journalArticle

Hanoun, Maher ; Eisele, Lewin ; Suzuki, Masako ; Greally, John M. ; Hüttmann, Andreas ; Aydin, Semra ; Scholtysik, René ; Klein-Hitpass, Ludger ; Dührsen, Ulrich ; Dürig, Jan. / Epigenetic silencing of the circadian clock gene CRY1 is associated with an indolent clinical course in chronic lymphocytic leukemia. In: PLoS One. 2012 ; Vol. 7, No. 3.
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