Supervisors info:
Μαρία-Χριστίνα Κυρτσώνη, Αναπληρώτρια Καθηγήτρια, Ιατρική, ΕΚΠΑ
Ευάγγελος Τέρπος, Καθηγητής, Ιατρική, ΕΚΠΑ
Πηνελόπη Κορκολοπούλου, Καθηγήτρια, Ιατρική, ΕΚΠΑ
Summary:
Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells, and accounts for 10% of all hematologic malignancies and 1% of all cancers. The diagnosis of multiple myeloma is made when bone marrow infiltration of clonal plasma cells ≥10% and monoclonal protein in the serum and/or urine are present, and clear end-organ damage under the acronym CRAB (hypercalcemia, renal insufficiency, anemia, bone disease) is attributable to the plasma cell proliferative disorder.
One hallmark of cancer is an unstable genome, which results from DNA damage. MM is characterized by genomic instability also, with certain genomic rearrangements being prognostic factors for the disease and patients’ clinical response. Eukaryotic cells developed intricate surveillance mechanisms to maintain their genome integrity and to repair DNA lesions. Following genotoxic stress, the evolutionary conserved DNA damage response (DDR) is activated and, in turn, coordinates DNA repair with cell-cycle events. However, the process of carcinogenesis cannot be attributed only the genetic alterations, but also involves epigenetic processes (DNA methylation, histone modifications and non-coding RNA deregulation).
Regulation of expression and activity of key DNA repair and checkpoint proteins is essential and is mediated partly by posttranslational modifications (PTM), such as acetylation, phosphorylation, or ubiquitination. Cross-talk between different PTMs is key for regulation of DNA repair pathways.
Acetylation, which is mediated by acetyltransferases (HAT) and histone deacetylases (HDAC), not only affects gene expression through its modulation of histone tails but also has recently been implicated in regulating non-histone proteins; among them several proteins which are involved in DNA damage and repair, such as p53, ATM, Ku70, and Exo1. Nowadays, a number of HDAC inhibitors have been developed both in pre-clinical and clinical studies, with some of them exhibiting significant anti-MM activities. Due to reversibility of epigenetic changes are reversible during the evolutionary process of carcinogenesis, the potency of epigenetic therapies seems to be of great importance.
The aim of the present work is the summary of all data on the role of HDAC inhibitors in DDR, the interference with each DNA repair mechanism, and the therapeutic implications of HDACi in MM disease.
