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.