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Rapid Disease Progression of Myelodysplastic Syndrome is Reflected in Transcriptomic and Functional Abnormalities of Bone Marrow MSCs

ABSTRACT: Current investigations of MDS-MSCs rely heavily on the clinical international prognostic scoring system (IPSS) or revised IPSS (IPSS-R) of MDS to classify them into either the low- or high-risk categories. This approach, however, suffers from shortcomings, as it is based on assessments of the hematopoietic parameters and may not capture important biological changes or predictors in MDS-MSCs during disease progression. Herein, to focus the investigation on discovering unique characteristics and dominant effects of MDS-MSCs in conditions of fast vs slow transforming disease, we retrospectively examined and selected MDS BM samples from these two patient categories: those with transformation to AML in less than 2 years (MDSfast) or after 2 years (MDSslow) following sample collection.

ORGANISM(S): Homo sapiens

PROVIDER: GSE280881 | GEO | 2025/10/31

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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Rapid Disease Progression of Myelodysplastic Syndrome is Reflected in Transcriptomic and Functional Abnormalities of Bone Marrow MSCs

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