TY - JOUR
T1 - Megakaryopoiesis impairment through acute innate immune signaling activation by azacitidine
AU - Okoye-Okafor, Ujunwa Cynthia
AU - Javarappa, Komal K.
AU - Tsallos, Dimitrios
AU - Saad, Joseph
AU - Yang, Daozheng
AU - Zhang, Chi
AU - Benard, Lumie
AU - Thiruthuvanathan, Victor J.
AU - Cole, Sally
AU - Ruiz, Stephen
AU - Tatiparthy, Madhuri
AU - Choudhary, Gaurav
AU - Defronzo, Stefanie
AU - Bartholdy, Boris A.
AU - Pallaud, Celine
AU - Ramos, Pedro Marques
AU - Shastri, Aditi
AU - Verma, Amit
AU - Heckman, Caroline A.
AU - Will, Britta
N1 - Publisher Copyright:
© 2022 Okoye-Okafor et al.
PY - 2022/11/7
Y1 - 2022/11/7
N2 - 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.
AB - 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.
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U2 - 10.1084/jem.20212228
DO - 10.1084/jem.20212228
M3 - Article
C2 - 36053753
AN - SCOPUS:85137164396
SN - 0022-1007
VL - 219
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 11
M1 - e20212228
ER -