Interleukin-6 Interweaves the Bone Marrow Microenvironment, Bone Loss, and Multiple Myeloma

The immune system is strongly linked to the maintenance of healthy bone. Inflammatory cytokines, specifically, are crucial to skeletal homeostasis and any dysregulation can result in detrimental health complications. Interleukins, such as interleukin 6 (IL-6), act as osteoclast differentiation modulators and as such, must be carefully monitored and regulated. IL-6 encourages osteoclastogenesis when bound to progenitors and can cause excessive osteoclastic activity and osteolysis when overly abundant. Numerous bone diseases are tied to IL-6 overexpression, including rheumatoid arthritis, osteoporosis, and bone-metastatic cancers. In the latter, IL-6 can be released with growth factors into the bone marrow microenvironment (BMM) during osteolysis from bone matrix or from cancer cells and osteoblasts in an inflammatory response to cancer cells. Thus, IL-6 helps create an ideal microenvironment for oncogenesis and metastasis. Multiple myeloma (MM) is a blood cancer that homes to the BMM and is strongly tied to overexpression of IL-6 and bone loss. The roles of IL-6 in the progression of MM are discussed in this review, including roles in bone homing, cancer-associated bone loss, disease progression and drug resistance. MM disease progression often includes the development of drug-resistant clones, and patients commonly struggle with reoccurrence. As such, therapeutics that specifically target the microenvironment, rather than the cancer itself, are ideal and IL-6, and its myriad of downstream signaling partners, are model targets. Lastly, current and potential therapeutic interventions involving IL-6 and connected signaling molecules are discussed in this review

New Bone Cell Type Identified as Driver of Drug Resistance in Multiple Myeloma: The Bone Marrow Adipocyte

Multiple myeloma (MM) is a hematological malignancy that is characterized by clonal proliferation of transformed plasma cells within the bone marrow (BM) and severe bone disease. Although MM cells are initially sensitive to many therapies, patients eventually relapse with refractory disease. Because MM cells show a dependency on the BM microenvironment for survival and proliferation, and BM adipocytes (BMAs) demonstrate a unique, endocrine signaling capacity and lipid composition, it is likely that there is cross-talk between MM cells and BMAs that leads to tumor support. Unlike the influences of osteoblasts and osteoclasts, the effect of BMAs on MM cells is poorly understood and few studies have investigated the relationship between bone marrow adipose tissue (BMAT) and cancer. We predict there to be a strong link between MAT and MM, as obesity is a risk factor for MM and also correlates with increased MAT in humans. Moreover, MAT has been shown to support other tumors and correlates with bone diseases such as osteoporosis, anorexia, and aging. Thus, we explored here the novel hypothesis that BMAs induce drug resistance in MM cells through direct cell-cell contact signaling and/or secreted signaling molecules

Investigation of the relationship between obesity, weight cycling, and tumor progression in murine myeloma models

We investigated this relationship in two murine myeloma models with a high fat diet (HFD) to induce obesity, and a diet cycling (DC) regimen to model weight cycling.https://knowledgeconnection.mainehealth.org/lambrew-retreat-2021/1025/thumbnail.jp

Inhibiting Fatty Acid Binding Protein Family Members Decreases Multiple Myeloma Cell Proliferation Through Effecting the myc Pathway

FABP inhibition leads to increased survival of myeloma bearing mice and decreased cell growth by inhibiting MYC signaling.https://knowledgeconnection.mainehealth.org/lambrew-retreat-2021/1016/thumbnail.jp

Multiple myeloma cells Graphs and Figures inhibit adipogenesis, increase senescencerelated and inflammatory gene transcript expression, and alter metabolism in preadipocytes

Myeloma cells alter metabolism & induce senescence in adipocyte-lineage cells, suggesting that senescence-associated proteins are involved in multiple myeloma.https://knowledgeconnection.mainehealth.org/lambrew-retreat-2021/1032/thumbnail.jp

Global Epigenetic Regulation of MicroRNAs in Multiple Myeloma

Epigenetic changes frequently occur during tumorigenesis and DNA hypermethylation may account for the inactivation of tumor suppressor genes in cancer cells. Studies in Multiple Myeloma (MM) have shown variable DNA methylation patterns with focal hypermethylation changes in clinically aggressive subtypes. We studied global methylation patterns in patients with relapsed/refractory MM and found that the majority of methylation peaks were located in the intronic and intragenic regions in MM samples. Therefore, we investigated the effect of methylation on miRNA regulation in MM. To date, the mechanism by which global miRNA suppression occurs in MM has not been fully described. In this study, we report hypermethylation of miRNAs in MM and perform confirmation in MM cell lines using bisulfite sequencing and methylation-specific PCR (MSP) in the presence or absence of the DNA demethylating agent 5-aza-2′-deoxycytidine. We further characterized the hypermethylation-dependent inhibition of miR-152, -10b-5p and -34c-3p which was shown to exert a putative tumor suppressive role in MM. These findings were corroborated by the demonstration that the same miRNAs were down-regulated in MM patients compared to healthy individuals, alongside enrichment of miR-152-, -10b-5p, and miR-34c-3p-predicted targets, as shown at the mRNA level in primary MM cells. Demethylation or gain of function studies of these specific miRNAs led to induction of apoptosis and inhibition of proliferation as well as down-regulation of putative oncogene targets of these miRNAs such as DNMT1, E2F3, BTRC and MYCBP. These findings provide the rationale for epigenetic therapeutic approaches in subgroups of MM

Guidelines for Biobanking of Bone Marrow Adipose Tissue and Related Cell Types: Report of the Biobanking Working Group of the International Bone Marrow Adiposity Society

Over the last two decades, increased interest of scientists to study bone marrow adiposity (BMA) in relation to bone and adipose tissue physiology has expanded the number of publications using different sources of bone marrow adipose tissue (BMAT). However, each source of BMAT has its limitations in the number of downstream analyses for which it can be used. Based on this increased scientific demand, the International Bone Marrow Adiposity Society (BMAS) established a Biobanking Working Group to identify the challenges of biobanking for human BMA-related samples and to develop guidelines to advance establishment of biobanks for BMA research. BMA is a young, growing field with increased interest among many diverse scientific communities. These bring new perspectives and important biological questions on how to improve and build an international community with biobank databases that can be used and shared all over the world. However, to create internationally accessible biobanks, several practical and legislative issues must be addressed to create a general ethical protocol used in all institutes, to allow for exchange of biological material internationally. In this position paper, the BMAS Biobanking Working Group describes similarities and differences of patient information (PIF) and consent forms from different institutes and addresses a possibility to create uniform documents for BMA biobanking purposes. Further, based on discussion among Working Group members, we report an overview of the current isolation protocols for human bone marrow adipocytes (BMAds) and bone marrow stromal cells (BMSCs, formerly mesenchymal), highlighting the specific points crucial for effective isolation. Although we remain far from a unified BMAd isolation protocol and PIF, we have summarized all of these important aspects, which are needed to build a BMA biobank. In conclusion, we believe that harmonizing isolation protocols and PIF globally will help to build international collaborations and improve the quality and interpretation of BMA research outcomes

The LIN28B/let-7 axis is a novel therapeutic pathway in Multiple Myeloma

MYC is a major oncogenic driver of Multiple Myeloma (MM) and yet almost no therapeutic agents exist that target MYC in MM. Here we report that the let-7 biogenesis inhibitor LIN28B correlates with MYC expression in MM and is associated with adverse outcome. We also demonstrate that the LIN28B/let-7 axis modulates the expression of MYC, itself a let-7 target. Further, perturbation of the axis regulates the proliferation of MM cells in vivo in a xenograft tumor model. RNA sequencing and gene set enrichment analyses of CRISPR-engineered cells further suggest that the LIN28/let-7 axis regulates MYC and cell cycle pathways in MM. We provide proof-of-principle for therapeutic regulation of MYC through let-7 with an LNA-GapmeR containing a let-7b mimic in vivo, demonstrating that high levels of let-7 expression repress tumor growth by regulating MYC expression. These findings reveal a novel mechanism of therapeutic targeting of MYC through the LIN28B/let-7 axis in MM that may impact other MYC dependent cancers as well