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Epigenetic Inactivation of the Circadian Clock Gene BMAL1 in Hematologic Malignancies

¹ Cancer Epigenetics and Biology Program and ² Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, L'Hospitalet, and ³ Institució Catalana de Recerca i Estudis Avançats, Catalonia, Spain; and ⁴ First Department of Internal Medicine, Sapporo Medical University School of Medicine and ⁵ Sapporo Medical University, Sapporo, Japan

Requests for reprints: Manel Esteller, Cancer Epigenetics and Biology Program (PEBC), 3rd Floor, Hospital Duran i Reynals, Avda. Gran Via 119-129, Km. 2.7, 08907 L'Hospitalet, Barcelona, Catalonia, Spain. Phone: 34-93-2607253; Fax: 34-93-2607219; E-mail: mesteller{at}iconcologia.net.

Disruption of circadian rhythms, daily oscillations in biological processes that are regulated by an endogenous clock, has been linked to tumorigenesis. Normal and malignant tissues often show asynchronies in cell proliferation and metabolic rhythms. Cancer chronotherapy takes biological time into account to improve the therapy. However, alterations of the circadian clock machinery genes have rarely been reported in human cancer. Herein, we show that the BMAL1 gene, a core component of the circadian clock, is transcriptionally silenced by promoter CpG island hypermethylation in hematologic malignancies, such as diffuse large B-cell lymphoma and acute lymphocytic and myeloid leukemias. We also describe how BMAL1 reintroduction in hypermethylated leukemia/lymphoma cells causes growth inhibition in colony assays and nude mice, whereas BMAL1 depletion by RNA interference in unmethylated cells enhances tumor growth. We also show that BMAL1 epigenetic inactivation impairs the characteristic circadian clock expression pattern of genes such as C-MYC, catalase, and p300 in association with a loss of BMAL1 occupancy in their respective promoters. Furthermore, the DNA hypermethylation–associated loss of BMAL1 also prevents the recruitment of its natural partner, the CLOCK protein, to their common targets, further enhancing the perturbed circadian rhythm of the malignant cells. These findings suggest that BMAL1 epigenetic inactivation contributes to the development of hematologic malignancies by disrupting the cellular circadian clock. [Cancer Res 2009;69(21):8447–54]

Key Words: Epigenetics • DNA methylation • Cancer • Circadian Clock