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Targeting IL-1b–mediated inflammatory signaling overcomes transfusion dependence in early-stage myelodysplastic syndromes

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-1b–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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE237148 | GEO | 2024/03/20

REPOSITORIES: GEO

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Project description:Deleterious somatic mutations in DNMT3A or TET2 are associated with clonal expansion of haematopoietic cells and higher risk of cardiovascular disease (CVD). In mice, most studies have indicated an over-activation of the inflammatory program in myeloid cells with reduced DNMT3A or TET2 expression. However, the effect of loss of function of DNMT3A and TET2 in human myeloid cells remains poorly understood. Here, we investigated the roles of DNMT3A and TET2 in normal human monocyte- derived macrophages (mDM), in mDM isolated from individuals with DNMT3A or TET2 mutations and in macrophages isolated from human atherosclerotic plaques. Using a combination of transcriptomic, epigenetic, and imaging assays, we provide evidence that, in addition to distinct roles in regulation of macrophage gene expression, DNMT3A and TET2 share a common role in maintaining mitochondrial DNA integrity by regulating the expression of Transcription Factor A, Mitochondria ( TFAM ). This shared function is dependent on interactions of DNMT3A and TET2 with RBPJ and ZNF143 at regulatory elements in the TFAM gene. Experimental reduction of DNMT3A or TET2 expression in normal human mDMs results in downregulation of TFAM, release of mtDNA into the cytoplasm and consequent activation of a type I interferon response mediated by cGAS. Single-cell RNA-seq analysis of mDMs from individuals with heterozygous loss-of-function mutations in DNMT3A and TET2 revealed a similar transcriptional signature. In addition, single-cell RNA-seq analysis of normal mDM and macrophages residing in human atherosclerotic plaques revealed higher expression of type I IFN signature genes specifically in cells with lower DNMT3A or TET2 expression. The production of IFN as a component of the type I IFN response induces activation of interferon-stimulated genes in neighbouring cells, representing a mechanism by which partial loss of function of DNMT3A or TET2 in a small fraction of cells could exert pathogenic effects in the artery wall. These findings suggest that targeting the type I IFN pathway may have therapeutic value in reducing risk of cardiovascular disease in patients with DNMT3A or TET2 mutations.

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Targeting IL-1b–mediated inflammatory signaling overcomes transfusion dependence in early-stage myelodysplastic syndromes

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