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

Abstract

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.

A Predictor Combining Clinical and Genetic Factors for AML1-ETO Leukemia Patients

“…Seyhan et al showed that RAS genes and identified their association with doxorubicin and etoposide sensitivity. They also found that GF2R, CTSA, and ATP6AP2 were gene biomarkers, which can subgroup AML patients into distinct good and bad prognostic groups (24). We try to find more drug-sensitive biomarker genes for AML-ETO patients and improve AML patient efficiency.…”

Serum Metabolomics Coupling With Clinical Laboratory Indicators Reveal Taxonomic Features of Leukemia

“…These findings about dyslipidemia suggest that the blood lipid profile of patients with leukemia may be a diagnostic/ prognostic factor in the treatment of acute leukemia. In the exploration of leukemia resistance to chemotherapy, some studies have found that renin-angiotensin system (RAS) gene can divide AML patients into different subtypes, and may also be a biomarker of AML drug sensitivity and prognosis (Turk et al, 2020). Excitingly, it has been reported that inhibition of RAS remodels the triacylglycerol network (Sas et al, 2021).…”

LncRNA-PAX8-AS1 Silencing Decreases Cell Viability, Enhances Apoptosis, and Suppresses Doxorubicin Resistance in Myeloid Leukemia via the miR-378g/ERBB2 Axis

“…The development of multidrug resistance (MDR) involves multiple mechanisms [ 5 ], which are ATP-binding cassette (ABC) overexpression-induced drug efflux pumps that reduce intracellular drug concentrations [ 6 ], FLT3 mutation [ 7 ], DNA repair abnormalities [ 8 ], apoptosis tolerance [ 5 ], and bone marrow microenvironment changes [ 9 ]. Doxorubicin (ADM) is a first-line chemotherapeutic drug used in AML [ 10 ] and has been recorded to mediate caspase activation and apoptotic DNA fragmentation to induce death of AML cells [ 11 ]. Resistance to ADM involves upregulation of proteins from the ABC superfamily to cause efflux of the drug in AML cells [ 12 ], which remains a significant obstacle to the successful treatment of AML.…”