3025 – AZACITIDINE INDUCES THROMBOCYTOPENIA VIA INHIBITION OF MEGAKARYOPOIESIS

Thrombocytopenia defined as platelet counts of Several studies evaluating the use of thrombopoietin receptor agonists (TPO-RA) for the clinical management of thrombocytopenia have shown promising clinical results. TPO-RA eltrombopag (EP) which has been effective as a single agent to raise platelet counts in MDS, but failed to stimulate platelet production in a phase III placebo-controlled clinical study when used in combination with AZA (NCT02158936). Here, we assessed the molecular and cellular mechanisms of AZA contributing to thrombocytopenia and interfering with TPO-RA mediated rescue. Our results demonstrate that AZA mediates the rapid induction of dsRNAs and activation of interferon type I (IFN-I) signaling in various hematopoietic cells, including stem and progenitor cells of healthy donors and MDS/AML. This engagement of IFN-I/STAT1/SOCS1 signaling resulted in significant inhibition of megakaryocytic progenitor growth and differentiation, independently of DNA hypomethylation and endogenous retroviruses. We show that the inhibitory effects of AZA on megakaryopoeisis can be counteracted through inhibition of IFN-I signaling, SOCS1 activation or P38 MAPK activity. Our findings provide evidence intercepting inhibition of TPO-R signaling by AZA-induced innate immune IFN-I pathway and thrombocytopenia.