Disregulation of genes making up the mammalian circadian clock has been associated with different forms of cancer. This study aimed to address how the circadian clock genes behave over the course of treatment for both the acute and chronic forms of leukemia and whether any could be used as potential biomarkers as a read-out for therapeutic efficacy. Expression profiling for both core and ancillary clock genes revealed that the majority of clock genes are down-regulated in acute myeloid leukemia patients, except for Cry2, which is up-regulated towards the end of treatment. A similar process was seen in acute lymphocytic leukemia patients; however, here, Cry2 expression came back up towards control levels upon treatment completion. In addition, all of the core clock genes were down-regulated in both chronic forms of leukemia (chronic myeloid leukemia and chronic lymphocytic leukemia), except for Cry2, which was not affected when the disease was diagnosed. Furthermore, the NAD(+) – dependent protein deacetylase Sirt1 has been proposed to have a dual role in both control of circadian clock circuitry and promotion of cell survival by inhibiting apoptotic pathways in cancer. We used a pharmacological-based approach to see whether Sirt1 played a role in regulating the circadian clock circuitry in both acute and chronic forms of leukemia. Our results suggest that interfering with Sirt1 leads to a partial restoration of BMAL1 oscillation in chronic myeloid leukemia patient samples. Furthermore, interfering with Sirt1 activity led to both the induction and repression of circadian clock genes in both acute and chronic forms of leukemia, which makes it a potential therapeutic target to either augment existing therapies for chronic leukemia or to act as a means of facilitating chronotherapy in order to maximize both the effectiveness of existing therapies and to minimize therapy-associated toxicity.

Skeletal development throughout the embryonic and postnatal phases is a dynamic process, based on bone remodeling and the balance between the activities of osteoclasts and osteoblasts modulating skeletal homeostasis. The Notch signaling pathway is a regulator of several developmental processes, and plays a crucial role in the development of the human skeleton by regulating the proliferation and differentiation of skeletal cells. The Delta Like-1 (DLL1) gene plays an important role in Notch signaling. We propose that an identified alteration in DLL1 protein may affect the downstream signaling. In this article, we present for the first time two siblings with a mutation in the DLL1 gene, presenting with congenital vertebral malformation. Using variable in silico prediction tools, it was predicted that the variant was responsible for the development of disease. Quantitative reverse-transcription polymerase chain reaction (PCR) for the Notch signaling pathway, using samples obtained from patients, showed a significant alteration in the expression of various related genes. Specifically, the expression of neurogenic locus notch homolog protein 1, SNW domain-containing protein 1, disintegrin, and metalloproteinase domain-containing proteins 10 and 17, was upregulated. In contrast, the expression of HEY1, HEY2, adenosine deaminase (ADA), and mastermind-like-1 (MAML-1) was downregulated. Furthermore, in a phosphokinase array, four kinases were significantly changed in patients, namely, p27, JANK1/2/3, mitogen- and stress-activated protein kinases 1 and 2, and focal adhesion kinase. Our results suggest an implication of a DLL1 defect related to the Notch signaling pathway, at least in part, in the morphologic abnormality observed in these patients. A limitation of our study was the low number of patients and samples. Further studies in this area are warranted to decipher the link between a DLL1 defect and skeletal abnormality.