Renin angiotensin system genes are biomarkers for personalized treatment of acute myeloid leukemia with Doxorubicin as well as etoposide

• DOI: 10.1371/journal.pone.0242497
• Publication Date: 2020-11-25T18:24:34Z
• Authors: Seyhan Turk; Can Turk; Muhammad Waqas Akbar; Baris Kucukkaraduman; Murat Isbilen; Secil Demirkol Canli; Umit Yavuz Malkan; Mufide Okay; Gulberk Ucar; Nilgun Sayinalp; Ibrahim Celaletti...; Ali Osmay Gure
• Keywords: 0301 basic medicine; Cytotoxicity; Science; Datasets as Topic; Tretinoin; Kaplan-Meier Estimate; Real-Time Polymerase Chain Reaction; Renin-Angiotensin System; Inhibitory Concentration 50; 03 medical and health sciences; Cell Line, Tumor; Antineoplastic Combined Chemotherapy Protocols; Humans; Computer Simulation; Precision Medicine; Etoposide; 2. Zero hunger; 0303 health sciences; Acute myeloid leukemia; Q; R; Cytarabine; Cancer drug discovery; Prognosis; 3. Good health; Leukemia, Myeloid, Acute; Gene Ontology; Nonlinear Dynamics; Doxorubicin; Drug Resistance, Neoplasm; Medicine; Gene expression; Renin-angiotensin system; Linear regression analysis; Biomarkers; Research Article

Despite the availability of various treatment protocols, response to therapy in patients with Acute Myeloid Leukemia (AML) remains largely unpredictable. Transcriptomic profiling studies have thus far revealed the presence of molecular subtypes of AML that are not accounted for by standard clinical parameters or by routinely used biomarkers. Such molecular subtypes of AML are predicted to vary in response to chemotherapy or targeted therapy. The Renin-Angiotensin System (RAS) is an important group of proteins that play a critical role in regulating blood pressure, vascular resistance and fluid/electrolyte balance. RAS pathway genes are also known to be present locally in tissues such as the bone marrow, where they play an important role in leukemic hematopoiesis. In this study, we asked if the RAS genes could be utilized to predict drug responses in patients with AML. We show that the combined in silico analysis of up to five RAS genes can reliably predict sensitivity to Doxorubicin as well as Etoposide in AML. The same genes could also predict sensitivity to Doxorubicin when tested in vitro. Additionally, gene set enrichment analysis revealed enrichment of TNF-alpha and type-I IFN response genes among sensitive, and TGF-beta and fibronectin related genes in resistant cancer cells. However, this does not seem to reflect an epithelial to mesenchymal transition per se. We also identified that RAS genes can stratify patients with AML into subtypes with distinct prognosis. Together, our results demonstrate that genes present in RAS are biomarkers for drug sensitivity and the prognostication of AML.