Contact of myeloma cells induces a characteristic transcriptome signature in skeletal precursor cells –Implications for myeloma bone disease

Abstract

Physical interaction of skeletal precursors with multiple myeloma cells has been shown to suppress their osteogenic potential while favoring their tumor-promoting features. Although several transcriptome analyses of myeloma patient-derived mesenchymal stem cells have displayed differences compared to their healthy counterparts, these analyses insufficiently reflect the signatures mediated by tumor cell contact, vary due to different methodologies, and lack results in lineage-committed precursors. To determine tumor cell contact-mediated changes on skeletal precursors, we performed transcriptome analyses of mesenchymal stem cells and osteogenic precursor cells cultured in contact with the myeloma cell line INA-6. Comparative analyses confirmed dysregulation of genes which code for known disease-relevant factors and additionally revealed upregulation of genes that are associated with plasma cell homing, adhesion, osteoclastogenesis, and angiogenesis. Osteoclast-derived coupling factors, a dysregulated adipogenic potential, and an imbalance in favor of anti-anabolic factors may play a role in the hampered osteoblast differentiation potential of mesenchymal stem cells. Angiopoietin-Like 4 (ANGPTL4) was selected from a list of differentially expressed genes as a myeloma cell contact-dependent target in skeletal precursor cells which warranted further functional analyses. Adhesion assays with full-length ANGPTL4-coated plates revealed a potential role of this protein in INA-6 cell attachment. This study expands knowledge of the myeloma cell contact-induced signature in the stromal compartment of myelomatous bones and thus offers potential targets that may allow detection and treatment of myeloma bone disease at an early stage.

Epigenetic‐Based Mechanisms of Osteoblast Suppression in Multiple Myeloma Bone Disease

“…In such a way, myeloma‐induced alterations of chromatin structure in BMSCs can be epigenetically propagated as a heritable memory regulating the transcriptional signature in the absence of continuous MM signals. Along with these observations, several analyses comparing the transcriptomic profile of BMSCs cocultured with MM cells and/or patient‐derived MM‐BMSCs to their healthy non‐myeloma counterparts have revealed clear differences . In this review, we discuss various chromatin‐based epigenetic mechanisms that contribute to osteogenic suppression and enhance adipogenic differentiation of BMSC progenitors in the context of MM bone disease (MMBD).…”

JAM-A as a prognostic factor and new therapeutic target in multiple myeloma

“…Herein, we investigated contact-induced receptors upon physical interaction of MM and bone cells. 20 We identified members of the junctional adhesion molecule (JAM) family and the chemokine receptor CXCR4 as contact-enhanced targets: first, 21 CXCR4 has been described as a useful theranostic target in MM patients; 22 second, JAM-A is associated with CXCR4; 23 and third, JAM-A was described to have an important role in hematopoietic stem cell biology. 24 These observations prompted us to investigate JAM-A in MM.…”

Semaphorin 4D correlates with increased bone resorption, hypercalcemia, and disease stage in newly diagnosed patients with multiple myeloma

“…Our findings are in accordance with the deregulation of bone metabolism in MM characterized by decreased osteoblast activity 1 . In a recent study, evaluating gene expression in skeletal precursor cells after 24 h co-culture with the MM cell line INA-6-altered transcriptome profiles of genes associated with bone metabolism, including Sema4D, were detected 24 . Indeed, MM cells seem to prevent osteoblast differentiation through a Sema4D-mediated mechanism 17 .…”