Poster Presenter

An innovative Epigenetic merge inTreatment of Leukemic Patients
Ghorab R.M. Farouk M. Kamel, MS; Neanaa H. Mohammad, MD

PURPOSE: Troubles anarchy that arise in treatment of Adult Acute Myeloid Leukemia, encompassing resistance to chemotherapy, short-term of DFS & early relapse due to MRD assessed a rational for targeting the tricky epigenetic aberrations in this complex disease. Epigenetic gene silencing due to aberrant promoter hypermethylation portrays a leukemogenic mechanism in (AML) that affects various molecular pathways. In order to improve prognosis & treatment, epigenetic therapy signified a rational that targets such easily reversible imperfection via inhibiting he DNA Methyltransferase1 (DNMT1) gene and reactivation of tumor suppressor genes. The mechanistic role of Dnmt1 in cellular transformation & growth regulation entailed the worth of Dnmt1 inhibitors for reversing the malignant phenotype of AML blasts. The present study represents a novel combination of Dnmt1 inhibitors: EGCG "in green tea" & the HDAC inhibitor valproic acid given parallel to the standard 3+7 protocol for 2 successive cycles. METHODS: 45 newly diagnosed AML patients were enrolled in this study, received treatment according to designed protocol, followed up for 2 years and compared to controls. Serum samples were assayed for the following: P15INK4B gene expression & methylation state using RT-PCR & MS-PCR techniques respectively. Dnmt1 activity using UV-based enzyme coupled assay. IL-6, TNFα, VEGF levels by ELISA. NF-κb using colorimetric NF-κb-DNA binding assay. Finally, for COX2, P65 protein level with western blot. RESULTS: Data indicated 37/45 (CR),7 (PR) &1 (RF)& elimination of MRD by 60%. A significant decrease in Dnmt1 activity (p<0.001). This decline in activity was able to reverse the P15INK4B methylation state by 58 %, re-express the silenced utter (p<0.02) and correlate significantly with decreased level of the pre-mentioned cytokines in a harmonized orchestra (p<0.01). Survival analyses showed rehearse of remission end-point, regression of predictor variables cumulative effect& high significant 2 years DFS (P=0. 009) & 95%. CONCLUSION: The proposed epi-drug combination when used as specified, distinctively reduced DNA MeTase activity, caused regression of cellular proliferation, switched the angiogenic phenotype & triggered apoptotic potential in AML cells. This was deciphered to suppression of tumor progression with better hematological & clinical response.