Scientific publications
IL-1β-mediated inflammatory signaling drives ineffective erythropoiesis in early-stage myelodysplastic syndromes. Scientific Publication
Vera Adema, Irene Ganan-Gomez, Feiyang Ma, Juan Jose Rodriguez-Sevilla, Kelly Chien, Hui Yang, Natthakan Thongon, Rashmi Kanagal-Shamanna, Sanam Loghavi, Guillermo Montalban-Bravo, Danielle Hammond, Yiqian Gu, Roselyn Tan, Lin Tan, Philip Lorenzi, Gheath Al-Atrash, Karen Clise-Dwyer, Rafael Bejar, Matteo Pellegrini, Guillermo Garcia-Manero, Simona Colla
Abstract
Myelodysplastic syndromes (MDS) are a group of incurable hematopoietic stem cell (HSC) neoplasms characterized by peripheral blood cytopenias and a high risk of progression to acute myeloid leukemia. MDS represent the final stage in a continuum of HSCs' genetic and functional alterations and are preceded by a premalignant phase, clonal cytopenia of undetermined significance (CCUS). Dissecting the mechanisms of CCUS maintenance may uncover therapeutic targets to delay or prevent malignant transformation.
Here, we demonstrate that DNMT3A and TET2 mutations, the most frequent mutations in CCUS, induce aberrant HSCs' differentiation towards the myeloid lineage at the expense of erythropoiesis by upregulating IL-1β-mediated inflammatory signaling and that canakinumab rescues red blood cell transfusion dependence in early-stage MDS patients with driver mutations in DNMT3A and TET2 . This study illuminates the biological landscape of CCUS and offers an unprecedented opportunity for MDS intervention during its initial phase, when expected survival is prolonged.
CITATION bioRxiv [Preprint]. 2023 Sep 30:2023.09.28.560018. doi: 10.1101/2023.09.28.560018.
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