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Megakaryopoiesis impairment through acute innate immune signaling activation by azacitidine
Ujunwa Cynthia Okoye-Okafor1,2, Komal K Javarappa3, Dimitrios Tsallos3
1Albert Einstein College of Medicine/Montefiore Medical Center, Department of Cell Biology, Bronx, NY.
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.
Insights
Azacitidine treatment for myeloid malignancies can worsen thrombocytopenia by activating type-I interferon signaling, which inhibits platelet production. Targeting this interferon pathway may improve platelet counts during therapy.
Area of Science:
- Hematology
- Immunology
- Molecular Biology
Background:
- Thrombocytopenia is common in myeloid malignancies like myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).
- Azacitidine (AZA) is a key treatment for transplant-ineligible MDS/AML patients but can worsen thrombocytopenia via an unknown mechanism.
Purpose of the Study:
- To investigate the mechanism behind Azacitidine-induced thrombocytopenia.
- To identify the role of type-I interferon (IFN-I) signaling in this adverse effect.
Main Methods:
- Analysis of megakaryocytic progenitors' response to AZA.
- Investigating IFN-I receptor expression and downstream signaling pathways (STAT1/SOCS1).
- Assessing the impact on thrombopoietin receptor (TPO-R) signaling.
Main Results:
- Azacitidine activates acute type-I interferon (IFN-I) signaling in megakaryocytic progenitors.
- This activation leads to premature attenuation of thrombopoietin receptor (TPO-R) signaling.
- IFN-I signaling suppresses megakaryocytic progenitor growth and differentiation, causing thrombocytopenia.
Conclusions:
- RNA demethylation and IFN-I signaling are root causes of AZA-induced thrombocytopenia.
- Mitigating TPO-R inhibitory innate immune signaling is a potential therapeutic strategy.
- Supporting platelet production early in AZA therapy is crucial.
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