Biology subjects

Agirre, X.

Publications and source records attributed to Agirre, X..

3 recordsLinked to original sources

bioRxiv2019

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

Multiple myeloma (MM) progression and myeloma-associated bone disease (MBD) are highly dependent on the bone marrow (BM) microenvironment, in particular on mesenchymal stromal cells (MSCs). MSCs from MM patients exhibit an abnormal transcriptional profile, suggesting that epigenetic alterations could be governing the tumor-promoting functions of MSCs and their prolonged osteoblast (OB) suppression in MM. In this study, we analyzed the DNA methylome of BM-derived MSCs from patients with monoclonal gammopathy of undetermined significance, smoldering myeloma and symptomatic MM at diagnosis in comparison with their normal counterparts. DNA methylation alterations were found at each of the myeloma stage in association with deregulated expression levels of Homeobox genes involved in osteogenic differentiation. Moreover, these DNA methylation changes were recapitulated in vitro by exposing MSCs from healthy individuals to MM plasma cells. Pharmacological targeting of DNMTs and G9a with the dual inhibitor CM-272, reverted the expression of aberrantly methylated osteogenic regulators and promoted OB differentiation of MSCs from myeloma patients. Most importantly, in a mouse model of bone marrow-disseminated MM, administration of CM-272 prevented tumor-associated bone loss and reduced tumor burden. Our results demonstrated that not only was aberrant DNA methylation a main contributor to bone formation impairment found in MM patients, but also its targeting by CM-272 was able to reverse MM-associated bone loss.\n\nKEY POINTS- Bone marrow-derived mesenchymal stromal cells (MSCs) from monoclonal gammopathy of undetermined significance, smoldering myeloma and myeloma patients exhibit an aberrant DNA methylome compared to their healthy counterparts.\n- These DNA methylation changes are associated with an altered expression of genes of the Homeobox loci that orchestrate osteogenic differentiation of mesenchymal precursors.\n- MM plasma cell-exposed healthy MSCs recapitulate the DNA methylation alterations observed in MSCs isolated from myeloma patients.\n- Dual targeting of DNMTs and the histone methyltransferase G9a with CM-272 not only controls MM tumor burden but also prevents myeloma-associated bone loss.

cancer biology↗

bioRxiv2019

Dynamics of genome architecture and chromatin function during human B cell differentiation and neoplastic transformation

Despite recent advances, the dynamics of genome architecture and chromatin function during human cell differentiation and its potential reorganization upon neoplastic transformation remains poorly characterized. Here, we integrate in situ Hi-C and nine additional omic layers to define and biologically characterize the dynamic changes in three-dimensional (3D) genome architecture across normal B cell differentiation and in neoplastic cells from different subtypes of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) patients. Beyond conventional active (A) and inactive (B) compartments, an integrative analysis of Hi-C data reveals the presence of a highly-dynamic intermediate compartment enriched in poised and polycomb-repressed chromatin. During B cell development, we detect that 28% of the compartments change at defined maturation stages and mostly involve the intermediate compartment. The transition from naive to germinal center B cells is associated with widespread chromatin activation, which mostly reverts into the naive state upon further maturation of germinal center cells into memory B cells. The analysis of CLL and MCL neoplastic cells points both to entity and subtype-specific alterations in chromosome organization. Remarkably, we observe that large chromatin blocks containing key disease-specific genes alter their 3D genome organization. These include the inactivation of a 2Mb region containing the EBF1 gene in CLL and the activation of a 6.1Mb region containing the SOX11 gene in clinically aggressive MCL. This study indicates that 3D genome interactions are extensively modulated during normal B cell differentiation and that the genome of B cell neoplasias acquires a tumor-specific 3D genome architecture.

genomics↗

bioRxiv2019

Chromatin activation as a unifying principle underlying pathogenic mechanisms in multiple myeloma

Multiple myeloma (MM) is a plasma cell neoplasm associated with a broad variety of genetic lesions. In spite of this genetic heterogeneity, MMs share a characteristic malignant phenotype whose underlying molecular basis remains poorly characterized. In the present study, we examined plasma cells from MM using a multi-epigenomics approach and demonstrated that when compared to normal B cells, malignant plasma cells showed an extensive activation of regulatory elements, in part affecting co-regulated adjacent genes. Among target genes upregulated by this process, we found members of the NOTCH, NFkB, mTOR1 signaling and p53 signaling pathways. Other activated genes included sets involved in osteoblast differentiation and response to oxidative stress, all of which have been shown to be associated with the MM phenotype and clinical behavior. We functionally characterized MM specific active distant enhancers controlling the expression of thioredoxin (TXN), a major regulator of cellular redox status, and in addition identified PRDM5 as a novel essential gene for MM. Collectively our data indicates that aberrant chromatin activation is a unifying feature underlying the malignant plasma cell phenotype.

cancer biology↗