Unit:
Faculty of MedicineLibrary of the School of Health Sciences
Dissertation committee:
Βασιλική Παππά Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Μαρία Αγγελοπούλου, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Νόρα-Αθηνά Βύνιου, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ (άρτι συνταγιοδοτηθείσα)
Σωτήριος Παπαγεωργίου, Επίκουρος Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Θεόδωρος Βασιλακόπουλος, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Κοντοπίδου Φλώρα, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Διαμαντόπουλος Παναγιώτης, Επίκουρος Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Original Title:
Μελέτη της παθογένειας των μυελικών κακοηθειών με έμφαση στους μηχανισμούς επιδιόρθωσης του DNA
Translated title:
Study of the pathogenicity of myeloid malignancies with focus on DNA damage repair mechanisms
Summary:
Acute Myeloid Leukemia (AML) is a life-threatening myeloid malignancy whose induction treatment consists of combination chemotherapy with idarubicin and cytarabine for fit patients. Treatment failures (primary resistance to treatment or disease relapse) are frequent, urging the need for the development of novel treatments for this disease.
The DNA Damage Response Mechanism (DDR) comprises numerous molecules and pathways intended to arrest the cell cycle until DNA damage is repaired or else drive the cell to apoptosis.
AML-derived cell lines after treatment with idarubicin and cytarabine were used for studying the expression profile of 84 DDR genes, through polymerase chain reaction (PCR) arrays. We chose 5 DDR genes (PPP1R15A, CDKN1A, GADD45A, GADD45G, and EXO1), which exhibited increased expression in live cells after chemotherapy treatment in vitro. Consequently, we studied their expression in 74 de novo AML patient and 30 control samples. All five DDR genes were overexpressed in AML samples with increasing cytogenetic risk. Moreover, we found PPP1R15A expression to be increased in AML compared to control samples.
Next, we performed PPP1R15A silencing in AML cell lines in two separate experiments using siRNA and CRISPR-cas9, respectively. Cell viability was not affected by PPP1R15A downregulation alone. However, it was markedly decreased upon treatment with Idarubicin and Cytarabine in both experiments compared to cell lines with preserved PPP1R15A expression.
Our findings highlight that DDR regulators demonstrate increased expression in patients with high cytogenetic risk possibly reflecting increased genotoxic stress. Especially, PPP1R15A is mainly involved in the recovery of the cells from stress. Its downregulation might be a safe and effective way to increase sensitivity to chemotherapy in this disease.
Main subject category:
Health Sciences
Keywords:
DNA damage response, DNA repair mechanism, PPP1R15A, Acute myeloid leukemia, Resistance mechanisms
Number of references:
269
