Molecular Mechanisms Of Primary Resistance To Azacitidine In Mds/Aml Patients - Data Of The Hellenic Mds Study Group

Introduction: Azacitidine (AZA) is a hypomethylating agent that at low doses acts by inhibiting DNA methyltranferase activity. AZA is approved and widely used for the treatment of MDS patients and patients with AML not candidate for intensive chemotherapy. Unfortunately, even after an initial response, almost all patients relapse and so far -with the exception of a few clinical parameters and genetic mutations weakly correlated with favorable AZA response- the exact mechanisms underlying primary AZA resistance remain largely unknown. On the other hand, over the last years accumulated data suggest that hypoxia, an important regulatory factor of both, physiological and malignant, hematopoiesis, is also involved in MDS pathogenesis (Hayashi et al., 2018), while high Hif-1α levels in MDS have been previously correlated with poor overall survival and disease progression (Tong et al., 2012). Moreover, our group recently investigated the association between Hif-1α and response to AZA therapy and found that AZA-responders present with higher Hif-1α mRNA expression compared to non-responders/stable disease patients, while logistic regression analysis showed that Hif-1α mRNA expression is an independent predictor of response to AZA therapy (unpublished data).