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Targeting aberrant DNA methylation in mesenchymal stromal cells as a treatment for myeloma bone disease

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE137419 | GEO | 2020/11/25

REPOSITORIES: GEO

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Targeting aberrant DNA methylation in mesenchymal stromal cells as a treatment for myeloma bone disease.

Project description:Multiple myeloma (MM) progression and myeloma-associated bone disease (MBD) are highly dependent on bone marrow mesenchymal stromal cells (MSCs). MM-MSCs exhibit abnormal transcriptomes, suggesting the involvement of epigenetic mechanisms governing their tumor-promoting functions and prolonged osteoblast suppression. Here, we identify widespread DNA methylation alterations of bone marrow-isolated MSCs from distinct MM stages, particularly in Homeobox genes involved in osteogenic differentiation that associate with their aberrant expression. Moreover, these DNA methylation changes are recapitulated in vitro by exposing MSCs from healthy individuals to MM cells. Pharmacological targeting of DNMTs and G9a with dual inhibitor CM-272 reverts the expression of hypermethylated osteogenic regulators and promotes osteoblast differentiation of myeloma MSCs. Most importantly, CM-272 treatment prevents tumor-associated bone loss and reduces tumor burden in a murine myeloma model. Our results demonstrate that epigenetic aberrancies mediate the impairment of bone formation in MM, and its targeting by CM-272 is able to reverse MBD.

| S-EPMC7813865 | biostudies-literature

Targeting aberrant DNA methylation in mesenchymal stromal cells as a treatment for myeloma bone disease [methylation]

Project description:Genome wide DNA methylation profiling of bone marrow-derived mesenchymal stromal cells from healthy donors (n=11), monoclonal gammopathy of undetermined significance (MGUS) (n=10), smoldering myeloma (SMM) (n=8), multiple myeloma (MM) (n=9) patients, and healthy donors exposed to the MM.1S cell line (n=3). The Illumina Infinium MethylationEPIC Beadchip was used to obtain DNA methylation profiles across approximately 850,000 CpGs in this cell type.

2020-11-25 | GSE137360 | GEO

Targeting aberrant DNA methylation in mesenchymal stromal cells as a treatment for myeloma bone disease [methylation II]

2020-11-25 | GSE137416 | GEO

Targeting aberrant DNA methylation in mesenchymal stromal cells as a treatment for myeloma bone disease [expression]

Project description:Gene expression profiling of bone marrow-derived mesenchymal stromal cells from healthy donors (n=8), monoclonal gammopathy of undetermined significance (MGUS) (n=10), smoldering myeloma (SMM) (n=10) and multiple myeloma (MM) (n=24) patients. Gene expression profile of MSCs was obtained using high density oligonucleotide microarrays (Human Gene 1.0 ST Array from Affymetrix).

2020-11-25 | GSE137369 | GEO

Targeting aberrant DNA methylation in mesenchymal stromal cells as a treatment for myeloma bone disease [methylation]

Project description:Targeting aberrant DNA methylation in mesenchymal stromal cells as a treatment for myeloma bone disease [methylation]

| PRJNA565237 | ENA

Targeting aberrant DNA methylation in mesenchymal stromal cells as a treatment for myeloma bone disease

Project description:Targeting aberrant DNA methylation in mesenchymal stromal cells as a treatment for myeloma bone disease

| PRJNA565409 | ENA

Targeting aberrant DNA methylation in mesenchymal stromal cells as a treatment for myeloma bone disease [methylation II]

Project description:Targeting aberrant DNA methylation in mesenchymal stromal cells as a treatment for myeloma bone disease [methylation II]

| PRJNA565411 | ENA

Targeting aberrant DNA methylation in mesenchymal stromal cells as a treatment for myeloma bone disease [expression]

Project description:Targeting aberrant DNA methylation in mesenchymal stromal cells as a treatment for myeloma bone disease [expression]

| PRJNA565253 | ENA

Multiple myeloma mesenchymal stromal cells: Contribution to myeloma bone disease and therapeutics.

Project description:Multiple myeloma is a hematological malignancy in which clonal plasma cells proliferate and accumulate within the bone marrow. The presence of osteolytic lesions due to increased osteoclast (OC) activity and suppressed osteoblast (OB) function is characteristic of the disease. The bone marrow mesenchymal stromal cells (MSCs) play a critical role in multiple myeloma pathophysiology, greatly promoting the growth, survival, drug resistance and migration of myeloma cells. Here, we specifically discuss on the relative contribution of MSCs to the pathophysiology of osteolytic lesions in light of the current knowledge of the biology of myeloma bone disease (MBD), together with the reported genomic, functional and gene expression differences between MSCs derived from myeloma patients (pMSCs) and their healthy counterparts (dMSCs). Being MSCs the progenitors of OBs, pMSCs primarily contribute to the pathogenesis of MBD because of their reduced osteogenic potential consequence of multiple OB inhibitory factors and direct interactions with myeloma cells in the bone marrow. Importantly, pMSCs also readily contribute to MBD by promoting OC formation and activity at various levels (i.e., increasing RANKL to OPG expression, augmenting secretion of activin A, uncoupling ephrinB2-EphB4 signaling, and through augmented production of Wnt5a), thus further contributing to OB/OC uncoupling in osteolytic lesions. In this review, we also look over main signaling pathways involved in the osteogenic differentiation of MSCs and/or OB activity, highlighting amenable therapeutic targets; in parallel, the reported activity of bone-anabolic agents (at preclinical or clinical stage) targeting those signaling pathways is commented.

| S-EPMC4131274 | biostudies-literature

Transcriptomic profile induced in bone marrow mesenchymal stromal cells after interaction with multiple myeloma cells: implications in myeloma progression and myeloma bone disease.

Project description:Despite evidence about the implication of the bone marrow (BM) stromal microenvironment in multiple myeloma (MM) cell growth and survival, little is known about the effects of myelomatous cells on BM stromal cells. Mesenchymal stromal cells (MSCs) from healthy donors (dMSCs) or myeloma patients (pMSCs) were co-cultured with the myeloma cell line MM.1S, and the transcriptomic profile of MSCs induced by this interaction was analyzed. Deregulated genes after co-culture common to both d/pMSCs revealed functional involvement in tumor microenvironment cross-talk, myeloma growth induction and drug resistance, angiogenesis and signals for osteoclast activation and osteoblast inhibition. Additional genes induced by co-culture were exclusively deregulated in pMSCs and predominantly associated to RNA processing, the ubiquitine-proteasome pathway, cell cycle regulation, cellular stress and non-canonical Wnt signaling. The upregulated expression of five genes after co-culture (CXCL1, CXCL5 and CXCL6 in d/pMSCs, and Neuregulin 3 and Norrie disease protein exclusively in pMSCs) was confirmed, and functional in vitro assays revealed putative roles in MM pathophysiology. The transcriptomic profile of pMSCs co-cultured with myeloma cells may better reflect that of MSCs in the BM of myeloma patients, and provides new molecular insights to the contribution of these cells to MM pathophysiology and to myeloma bone disease.

| S-EPMC4226683 | biostudies-literature

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