MBGE SEMINAR by Çağatay SerdaroğluAuthor: COLLEGE OF SCIENCES
Location: SCI 103
KOÇ UNIVERSITY MBGE SEMINAR
Title : Identification of resistance mechanisms in AML versus Sorafenib treatment
Date : February 17, 2017 Friday
Time : 10:00
Place : SCI 103
Abstract : Acute myeloid leukemia (AML) is a myelodysplastic syndrome leading to the production of immature myeloid cells on the cost of healthy blood elements like thrombocytes and erythrocytes. AML is a very severe form of leukemia whose survival rate varies between 10-40%. It is an aggressive and genetically heterogeneous disease which initially can be treated with chemotherapy. However, a specific feature of AML is its recurrence in a chemotherapy resistant form. For these reasons, AML requires a more detailed understanding of its molecular biology. Fms-related tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase expressed on hematopoietic progenitors and on most leukemic myeloblasts. FLT3 internal tandem duplications (FLT3-ITDs) are seen in approximately 30% of patients with de novo AML and patients with FLT3-ITD have a poor prognosis (PMID:11535508, 12393388). Clinicians mainly focus on FLT3 inhibition as an additional treatment to chemotherapy. Most of the FLT3 inhibitors are still on trial phase. Sorafenib is a multi-kinase inhibitor that has the potential to stop blast cell proliferation for a short period. However, successful blast reduction in FLT3-ITD driven AML with Sorafenib is only of short duration as AML cells develop resistance towards Sorafenib.
In this study we used the MV4-11 cell line with an FLT3-ITD mutation as a model to identify resistance mechanisms in AML cells. Therefore, we treated the cell 5nM of Sorafenib chronically. We would like to figure out how cells become resistant to Sorafenib treatment analysing their secretome and surface proteome profiles to identify proteins that are decreased or increased in their expression. Potential resistance mechanisms are upregulation of FLT3 itself, increased expression of alternative receptor tyrosine kinases, activation of NF kappa B signalling and increased efflux of Sorafenib by membrane transporters.