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Myelodysplastic syndrome marrow stroma shows widespread aberrant hypermethylation that is abrogated by treatment with DNMT inhibitors

ABSTRACT: The marrow microenvironment contributes to the pathogenesis of ineffective hematopoiesis in Myelodysplastic Syndromes (MDS). Since mutations and cytogenetic alterations are generally not present in marrow stromal cells, we hypothesized that epigenetic alterations may be responsible for altered stroma functionin MDS. Global DNA methylation of MDS marrow-derived stroma was analyzed by HELP assay and compared to healthy controls. MDS stroma showed aberrant hypermethylation that preferentially occurred outside of CpG islands and involved important signaling pathways.Comparison with stroma derived from 5-Azacytidine (5-Aza) treated MDS patients revealed abrogation of aberrant methylation in treated samples. Integrative expression analysis revealed that the WNT pathway was epigenetically dysregulated in MDS stroma, and the WNT antagonists FRZB and SFRP1 were aberrantly hypermethylated and underexpressed. These epigenetic changes were validated ina co-culture model of stroma and leukemic cells and in an independent set of MDS samples. Importantly, 5-Aza treatment of MDS stroma enhanced hematopoietic activity and erythroid differentiationfrom co-cultured healthy CD34+ cells. These results reveal widespread aberrant epigenetic changes in the MDS marrow microenvironment and demonstrate that DNA methyl transferase inhibitors alter the epigenomic profiles of stromal cells, potentiallycontributing to theirtherapeutic efficacy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE60233 | GEO | 2015/05/20

SECONDARY ACCESSION(S): PRJNA257803

REPOSITORIES: GEO

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Project description:Ineffective hematopoiesis is a hallmark of myelodysplastic syndromes (MDS). Hematopoietic alterations in MDS patients strictly correlate with microenvironment dysfunctions, eventually affecting also the mesenchymal stromal cells (MSCs) compartment. Stromal cells are indeed epigenetically reprogrammed to cooperate with leukemic cells and propagate the disease as "tumor unit"; therefore, changes on MSCs epigenetic profile might contribute to the hematopoietic perturbations typical of MDS. Here, we unveil that the histone variant macroH2A1 (mH2A1) regulates the crosstalk between epigenetics and inflammation in MDS-MSCs, potentially affecting their hematopoietic support ability. We show that the mH2A1 splicing isoform mH2A1.1 accumulates in MDS-MSCs, correlating with the expression of the Toll-like receptor 4 (TLR4), an important pro-tumor activator of MSC phenotype associated to a pro-inflammatory behavior. MH2A1.1-TLR4 axis was further investigated in HS-5 stromal cells after ectopic mH2A1.1 overexpression (mH2A1.1-OE). Proteomic data confirmed the activation of a pro-inflammatory signature associated to TLR4 and nuclear factor kappa B (NFkB) activation. Moreover, mH2A1.1-OE proteomic profile identified several upregulated proteins associated to DNA and histones hypermethylation, including S-adenosylhomocysteine hydrolase, a strong inhibitor of DNA methyltransferase and of the methyl donor S-adenosyl-methionine (SAM). HPLC analysis confirmed higher SAM/SAH ratio along with a metabolic reprogramming. Interestingly, an increased LDHA nuclear localization was detected both in mH2A1.1-OE cells and MDS-MSCs, probably depending on MSC inflammatory phenotype. Finally, coculturing healthy mH2A1-OE MSCs with CD34+ cells, we found a significant reduction in the number of CD34+ cells, which was reflected in a decreased number of colony forming units (CFU -Cs). These results suggest a key role of mH2A1.1 in driving the crosstalk between epigenetic signaling, inflammation and cell metabolism networks in MDS-MSCs.

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Myelodysplastic syndrome marrow stroma shows widespread aberrant hypermethylation that is abrogated by treatment with DNMT inhibitors

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