biostudies-literatureMei YRobert H. Lurie Comprehensive Cancer CenterCongressionally Directed Medical Research ProgramsNational Institute of Diabetes and Digestive and Kidney DiseasesNIDDK NIH HHSNHLBI NIH HHSNational Heart and Lung InstituteLeukemia and Lymphoma Societye152673https://www.ebi.ac.uk/biostudies/studies/S-EPMC9435651biostudies-literatureUnknown132(17)Myelodysplastic syndromes (MDS) are age-related myeloid neoplasms with increased risk of progression to acute myeloid leukemia (AML). The mechanisms of transformation of MDS to AML are poorly understood, especially in relation to the aging microenvironment. We previously established an mDia1/miR-146a double knockout (DKO) mouse model phenocopying MDS. These mice develop age-related pancytopenia with oversecretion of proinflammatory cytokines. Here, we found that most of the DKO mice underwent leukemic transformation at 12-14 months of age. These mice showed myeloblast replacement of fibrotic bone marrow and widespread leukemic infiltration. Strikingly, depletion of IL-6 in these mice largely rescued the leukemic transformation and markedly extended survival. Single-cell RNA sequencing analThe Journal of clinical investigationBone marrow-confined IL-6 signaling mediates the progression of myelodysplastic syndromes to acute myeloid leukemia.PMC9435651R01 HL150729R01-DK124220Translational Bridge GrantR01 HL148012R01-HL150729R01-HL148012CA140119Scholar AwardR01 DK124220Yang JXia ZZhang DXie XLu XMei YLi EHan XDong LZou CAltman JKSukhanova MJi PLiu YMa AVerma ALi ZRen KBao HTariq HAbaza YfalseBone marrow-confined IL-6 signaling mediates the progression of myelodysplastic syndromes to acute myeloid leukemia.Myelodysplastic syndromes (MDS) are age-related myeloid neoplasms with increased risk of progression to acute myeloid leukemia (AML). The mechanisms of transformation of MDS to AML are poorly understood, especially in relation to the aging microenvironment. We previously established an mDia1/miR-146a double knockout (DKO) mouse model phenocopying MDS. These mice develop age-related pancytopenia with oversecretion of proinflammatory cytokines. Here, we found that most of the DKO mice underwent leukemic transformation at 12-14 months of age. These mice showed myeloblast replacement of fibrotic bone marrow and widespread leukemic infiltration. Strikingly, depletion of IL-6 in these mice largely rescued the leukemic transformation and markedly extended survival. Single-cell RNA sequencing anal2022-01-01T00:00:00Z2022 Sep2026-05-28T03:28:00.978Z2025-02-19T00:44:01.081ZS-EPMC94356513590079410.1172/JCI152673