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  • Megakaryopoiesis impairment through acute innate immune signaling activation by azacitidine.

Megakaryopoiesis impairment through acute innate immune signaling activation by azacitidine.

The Journal of experimental medicine (2022-09-03)
Ujunwa Cynthia Okoye-Okafor, Komal K Javarappa, Dimitrios Tsallos, Joseph Saad, Daozheng Yang, Chi Zhang, Lumie Benard, Victor J Thiruthuvanathan, Sally Cole, Stephen Ruiz, Madhuri Tatiparthy, Gaurav Choudhary, Stefanie DeFronzo, Boris A Bartholdy, Celine Pallaud, Pedro Marques Ramos, Aditi Shastri, Amit Verma, Caroline A Heckman, Britta Will
ABSTRACT

Thrombocytopenia, prevalent in the majority of patients with myeloid malignancies, such as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), is an independent adverse prognostic factor. Azacitidine (AZA), a mainstay therapeutic agent for stem cell transplant-ineligible patients with MDS/AML, often transiently induces or further aggravates disease-associated thrombocytopenia by an unknown mechanism. Here, we uncover the critical role of an acute type-I interferon (IFN-I) signaling activation in suppressing megakaryopoiesis in AZA-mediated thrombocytopenia. We demonstrate that megakaryocytic lineage-primed progenitors present IFN-I receptors and, upon AZA exposure, engage STAT1/SOCS1-dependent downstream signaling prematurely attenuating thrombopoietin receptor (TPO-R) signaling and constraining megakaryocytic progenitor cell growth and differentiation following TPO-R stimulation. Our findings directly implicate RNA demethylation and IFN-I signal activation as a root cause for AZA-mediated thrombocytopenia and suggest mitigation of TPO-R inhibitory innate immune signaling as a suitable therapeutic strategy to support platelet production, particularly during the early phases of AZA therapy.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
SB 203580, InSolution, ≥98%, 1 mg/ml, reversible inhibitor of p38 MAP kinase
Roche
DAPI, 4′,6-Diamidine-2′-phenylindole dihydrochloride
Sigma-Aldrich
5-Aza-2′-deoxycytidine, ≥97%