Fc Receptor Targeting Reduces Bone Disease in a Pre-Clinical Model of Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3011-3011
Author(s):  
Mark T Williams ◽  
Katya Thümmler ◽  
Susan Kitson ◽  
Richard Soutar ◽  
Carl S Goodyear
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Bone Disease ◽  
Molecular Mechanisms ◽  
Signalling Pathways ◽  
Micro Ct ◽  
Cell Injection ◽  
Clinical Model ◽  
Rank Gene

Abstract Background: Multiple Myeloma (MM) is currently incurable, with a median survival of 5-7 years post diagnosis. MM-associated bone disease (MM-OBD), represents a major cause of morbidity and mortality in MM patients. Despite current therapies for MM-OBD exhibiting significant potential (e.g. Zoledronate), their clinical use has been restricted due to severe treatment associated toxicities. Safe novel therapies for MM-OBD are therefore crucially required. Molecular crosstalk between receptor activator of nuclear factor Kappa B ligand (RANKL), present on and secreted by MM plasma cells, and its corresponding receptor (RANK) on osteoclast precursors (OCPs), represents a key mechanism driving osteoclastogenesis and subsequent bone pathology in MM. Our previous studies have demonstrated that Fc receptor (FcR)-mediated signals can inhibit RANKL induced osteoclastogenesis in vitro1. In addition, findings from preliminary studies show that FcR-mediated signalling in pre-osteoclasts can reduce MM plasma cell driven osteoclastogenesis in vitro. Further interrogation of the underlying molecular mechanisms show that FcR-mediated signals profoundly reduce RANK transcript, and subsequent protein expression, in pre-osteoclasts. However, the effects of FcR engagement on MM-OBD in vivo, and the FcR elicited signalling pathways responsible for inhibition of RANK expression have still to be elucidated. Aims: This study aimed to determine the in vivo potential of FcR engagement to treat bone disease in a pre-clinical model of MM. Additionally, the mechanisms underlyingFcR-mediated down-regulation of RANK expression in OCPs were interrogated. Methods: The well-characterised 5TGM1 murine model of MM, together with micro-computed topography (micro-CT), were used to evaluate the effect of FcR engagement on MM-OBD. FcR stimulation was achieved by I.P. injecting mice (every other day, following 5TGM1 I.V. cell injection), with 100 μg/ml of Protein A derived from Staphylococcus aureus (SpA). SpA has been shown to form small immune complexes (SICs) through its affinity for endogenous IgG, which in turn binds to FcγR1 receptors on monocytes and pre-OCs1. Additionally, the potential involvement of FcR signalling pathways in the down-regulation of RANK in healthy and MM-derived human OCPs was determined via immunoblotting and the use of signalling pathway inhibitors. Results: Twenty six days post-myeloma cell injection, micro-CT analysis of femurs revealed that mice receiving PBS (vehicle control, n=5) exhibited a significant decrease in bone morphmetric parameters consistent with bone erosion compared to non-myeloma bearing mice (n=3); trabecullar bone volume [BV/TV] = 2.673 vs. 3.449, p=0.034; trabecullar number [Tb.N] = 0.0035 vs. 0.0042, p=0.0041; trabecullar pattern factor [Tb.Pf] = 0.2329 vs. 0.2033, p=0.0393. Importantly, myeloma bearing mice (n=5) receiving SpA, were protected from MM-OBD. In human OCPs (sourced from healthy individuals and MM patients), FcR engagement substantially activated SyK, MEK-ERK1/2, and PI3K signaling cascades. However, inhibition of these pathways failed to restore RANK transcript levels. Discussion: These findings demonstrate novel mechanisms of RANK gene expression regulation in healthy and MM OCPs, with Fc receptors representing a potential therapeutic strategy for MM-OBD. Further studies will aim to elucidate the molecular mechanisms responsible for FcR-mediated regulation of RANK gene expression. 1. MacLellan, L. M. et al. Co-opting endogenous immunoglobulin for the regulation of inflammation and osteoclastogenesis in humans and mice. Arthritis Rheum.63, 3897-3907 (2011). Disclosures No relevant conflicts of interest to declare.

The Mechanisms Behind the Biological Activity of Flavonoids

2019 ◽  
Vol 26 (39) ◽  
pp. 6976-6990 ◽  
Author(s):  
Ana María González-Paramás ◽  
Begoña Ayuda-Durán ◽  
Sofía Martínez ◽  
Susana González-Manzano ◽  
Celestino Santos-Buelga
Keyword(s):  
Gene Expression ◽  
Biological Activity ◽  
Phenolic Compounds ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Radical Scavenging ◽  
Model Organism ◽  
Stress Theory ◽  
Radical Scavenging Properties

: Flavonoids are phenolic compounds widely distributed in the human diet. Their intake has been associated with a decreased risk of different diseases such as cancer, immune dysfunction or coronary heart disease. However, the knowledge about the mechanisms behind their in vivo activity is limited and still under discussion. For years, their bioactivity was associated with the direct antioxidant and radical scavenging properties of phenolic compounds, but nowadays this assumption is unlikely to explain their putative health effects, or at least to be the only explanation for them. New hypotheses about possible mechanisms have been postulated, including the influence of the interaction of polyphenols and gut microbiota and also the possibility that flavonoids or their metabolites could modify gene expression or act as potential modulators of intracellular signaling cascades. This paper reviews all these topics, from the classical view as antioxidants in the context of the Oxidative Stress theory to the most recent tendencies related with the modulation of redox signaling pathways, modification of gene expression or interactions with the intestinal microbiota. The use of C. elegans as a model organism for the study of the molecular mechanisms involved in biological activity of flavonoids is also discussed.

Impact of Natural Dietary Agents on Multiple Myeloma Prevention and Treatment: Molecular Insights and Potential for Clinical Translation

2020 ◽  
Vol 27 (2) ◽  
pp. 187-215 ◽  
Author(s):  
Lavinia Raimondi ◽  
Angela De Luca ◽  
Gianluca Giavaresi ◽  
Agnese Barone ◽  
Pierosandro Tagliaferri ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Multiple Myeloma ◽  
Natural Products ◽  
Bone Disease ◽  
Molecular Mechanisms ◽  
Plasma Cells ◽  
Hematologic Malignancy ◽  
Signal Transduction Pathways ◽  
Pharmacologically Active ◽  
Dietary Agents

: Chemoprevention is based on the use of non-toxic, pharmacologically active agents to prevent tumor progression. In this regard, natural dietary agents have been described by the most recent literature as promising tools for controlling onset and progression of malignancies. Extensive research has been so far performed to shed light on the effects of natural products on tumor growth and survival, disclosing the most relevant signal transduction pathways targeted by such compounds. Overall, anti-inflammatory, anti-oxidant and cytotoxic effects of dietary agents on tumor cells are supported either by results from epidemiological or animal studies and even by clinical trials. : Multiple myeloma is a hematologic malignancy characterized by abnormal proliferation of bone marrow plasma cells and subsequent hypercalcemia, renal dysfunction, anemia, or bone disease, which remains incurable despite novel emerging therapeutic strategies. Notably, increasing evidence supports the capability of dietary natural compounds to antagonize multiple myeloma growth in preclinical models of the disease, underscoring their potential as candidate anti-cancer agents. : In this review, we aim at summarizing findings on the anti-tumor activity of dietary natural products, focusing on their molecular mechanisms, which include inhibition of oncogenic signal transduction pathways and/or epigenetic modulating effects, along with their potential clinical applications against multiple myeloma and its related bone disease.

Serial analysis of gene expression (SAGE) during porcine embryo development

2004 ◽  
Vol 16 (2) ◽  
pp. 87 ◽  
Author(s):  
Le Ann Blomberg ◽  
Kurt A. Zuelke
Keyword(s):  
Gene Expression ◽  
Functional Genomics ◽  
Embryo Development ◽  
Molecular Mechanisms ◽  
Physiological Role ◽  
Transgenic Animals ◽  
Specific Gene ◽  
Research Strategies

Functional genomics provides a powerful means for delving into the molecular mechanisms involved in pre-implantation development of porcine embryos. High rates of embryonic mortality (30%), following either natural mating or artificial insemination, emphasise the need to improve the efficiency of reproduction in the pig. The poor success rate of live offspring from in vitro-manipulated pig embryos also hampers efforts to generate transgenic animals for biotechnology applications. Previous analysis of differential gene expression has demonstrated stage-specific gene expression for in vivo-derived embryos and altered gene expression for in vitro-derived embryos. However, the methods used to date examine relatively few genes simultaneously and, thus, provide an incomplete glimpse of the physiological role of these genes during embryogenesis. The present review will focus on two aspects of applying functional genomics research strategies for analysing the expression of genes during elongation of pig embryos between gestational day (D) 11 and D12. First, we compare and contrast current methodologies that are being used for gene discovery and expression analysis during pig embryo development. Second, we establish a paradigm for applying serial analysis of gene expression as a functional genomics tool to obtain preliminary information essential for discovering the physiological mechanisms by which distinct embryonic phenotypes are derived.

scholarly journals Tumor Cell Gene Expression Changes Following Short-term In vivo Exposure to Single Agent Chemotherapeutics are Related to Survival in Multiple Myeloma

2008 ◽  
Vol 14 (15) ◽  
pp. 4821-4829 ◽  
Author(s):  
Bart Burington ◽  
Bart Barlogie ◽  
Fenghuang Zhan ◽  
John Crowley ◽  
John D. Shaughnessy
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Tumor Cell ◽  
Single Agent ◽  
Short Term ◽  
Cell Gene Expression ◽  
Cell Gene

MIP-1α (CCL3) is a downstream target of FGFR3 and RAS-MAPK signaling in multiple myeloma

Blood ◽  
2006 ◽  
Vol 108 (10) ◽  
pp. 3465-3471 ◽  
Author(s):  
Esther Masih-Khan ◽  
Suzanne Trudel ◽  
Carla Heise ◽  
Zhihua Li ◽  
Joshua Paterson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Bone Disease ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Transcriptional Response ◽  
Mapk Signaling ◽  
Growth And Survival ◽  
Ras Mutations ◽  
Downstream Target

Abstract Overexpression of fibroblast growth factor receptor 3 (FGFR3) is a hallmark of t(4;14) multiple myeloma (MM). To dissect the mechanism of FGFR3 oncogenesis in MM, we used 3 FGFR selective kinase inhibitors—CHIR258, PD173074, and SU5402—and FGFR3-specific siRNA to modulate FGFR3 activity. Conversely, the ligand FGF was used to stimulate FGFR3 function in human MM cells. The transcriptional response to FGFR3 modification was recorded, and gene expression changes common to all 5 modifiers were documented. Ten genes were commonly regulated. Macrophage inflammatory protein-1 alpha (MIP-1α) was the single most differentially altered gene. MIP-1 α promoter function, gene expression, and protein secretion were each down-regulated following inhibition of FGFR3 signaling. Down-regulation of MIP-1 α was not, however, observed following FGFR3 inhibition in MM cells with RAS mutations implicating RAS-MAPK in MIP-1 α regulation. As confirmation, inhibition of ERK1 also down-regulated MIP-1 α in FGFR3 inhibitor-resistant cells harboring RAS mutations. MIP-1 α is implicated in the survival and proliferation of MM cells and the pathogenesis of MM bone disease. Our observation is the first to directly link an initiating IgH translocation not only to MM-cell growth and survival but also to the disease-associated bone disease.

scholarly journals The Ubiquitin Carboxyl Hydrolase BAP1 Forms a Ternary Complex with YY1 and HCF-1 and Is a Critical Regulator of Gene Expression

2010 ◽  
Vol 30 (21) ◽  
pp. 5071-5085 ◽  
Author(s):  
Helen Yu ◽  
Nazar Mashtalir ◽  
Salima Daou ◽  
Ian Hammond-Martel ◽  
Julie Ross ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ternary Complex ◽  
Transcriptional Control ◽  
Molecular Mechanisms ◽  
Mitochondrial Protein ◽  
Coiled Coil ◽  
Dependent Manner ◽  
Cellular Processes ◽  
Rich Domain

ABSTRACT The candidate tumor suppressor BAP1 is a deubiquitinating enzyme (DUB) involved in the regulation of cell proliferation, although the molecular mechanisms governing its function remain poorly defined. BAP1 was recently shown to interact with and deubiquitinate the transcriptional regulator host cell factor 1 (HCF-1). Here we show that BAP1 assembles multiprotein complexes containing numerous transcription factors and cofactors, including HCF-1 and the transcription factor Yin Yang 1 (YY1). Through its coiled-coil motif, BAP1 directly interacts with the zinc fingers of YY1. Moreover, HCF-1 interacts with the middle region of YY1 encompassing the glycine-lysine-rich domain and is essential for the formation of a ternary complex with YY1 and BAP1 in vivo. BAP1 activates transcription in an enzymatic-activity-dependent manner and regulates the expression of a variety of genes involved in numerous cellular processes. We further show that BAP1 and HCF-1 are recruited by YY1 to the promoter of the cox7c gene, which encodes a mitochondrial protein used here as a model of BAP1-activated gene expression. Our findings (i) establish a direct link between BAP1 and the transcriptional control of genes regulating cell growth and proliferation and (ii) shed light on a novel mechanism of transcription regulation involving ubiquitin signaling.

Peripheral Blood Cells from Multiple Myeloma Patients Show Increased Osteoclast and Decreased Osteoblast Gene Expression.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5098-5098
Author(s):  
Melinda S. Gordon ◽  
Ariana M. Berenson ◽  
Charles B. Drucker ◽  
Matthew Katz ◽  
Hee Jin Lee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Alkaline Phosphatase ◽  
Bone Disease ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Bisphosphonate Treatment ◽  
Rt Pcr ◽  
Circulating Cells ◽  
Osteolytic Bone Disease

Abstract Bone resorption leading to osteolytic bone disease is characteristic of multiple myeloma (MM). Recent studies show the presence of bone-resorbing osteoclasts and bone-forming osteoclasts in the circulation, and these cells may correlate with bone disease and change with anti-bone resorptive therapies. We have investigated whether there is an imbalance in the expression of osteoblast and osteoclast genes in the peripheral blood mononuclear cells (PBMCs) from MM patients relative to normal age-matched controls and the effect of bisphosphonate treatment on the expression of these genes. We analyzed the expression of a panel of osteoblast-related (bone alkaline phosphatase [bone AP], bone morphogenic protein 2 [BMP2], collagen I and osteocalcin) and osteoclast-related (b3 integrin, calcitonin, receptor for activation of nuclear factor kappa B [RANK] and tartrate-resistant alkaline phosphatase [TRAP]) genes by semi-quantitative RT-PCR on total RNA isolated from PBMCs obtained following density gradient separation. We demonstrated that the expression of the osteoblast-related gene BMP2 was reduced in eight of nine MM patients when compared with normal donors. In marked contrast, three osteoclast-related genes, b3 integrin, RANK and TRAP, were more highly expressed in all nine MM patients compared to the normal donors; only calcitonin expression was similar to the control subjects. Interestingly, patients receiving bisphosphonate treatment appeared to show increased osteoblast gene expression with higher amounts of bone AP, BMP2 and osteocalcin RNA compared to the patients not receiving anti-bone resorptive therapy. However, there was no alteration in the level of the RNA in any of the four osteoclast genes compared to patients not receiving anti-bone resorptive therapy. We are extending our analysis to a larger panel of MM patients in order to determine the relationship between these circulating cells and bone disease, overall clinical status and change in their levels with anti-bone resorptive therapy. In addition, we are also investigating whether there exist larger and smaller numbers of circulating osteoclasts and osteoblasts, respectively, in MM patients, or whether these circulating cells show alteration of their expression of these genes. Our semi-quantitative RT-PCR results are being correlated with immunohistochemical staining results from osteoblast and osteoclast markers obtained on PBMCs from MM and normal subjects. These studies provide evidence that the number of circulating osteoblasts and osteoclasts is altered in patients with MM, and also may suggest that bisphosphonate therapy may also be associated with changes in these cell populations.

An Erythoid-Specific Component of the Rhesus Stage Selector Protein, rNF-E4, Modulates γ-Globin Gene Expression Specifically.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1599-1599
Author(s):  
Ruiqiong Wu ◽  
Aurelie Desgardin ◽  
Stephen M. Jane ◽  
John M. Cunningham
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Globin Gene ◽  
Primate Species ◽  
Pcr Analysis ◽  
Gene Promoters ◽  
Fetal Stage ◽  
Globin Gene Expression ◽  
Selector Protein

Abstract Understanding the molecular mechanisms that regulate γ-globin gene expression is essential for development of new therapeutic strategies for individuals with sickle cell disease and β-thalassemia. We have previously identified a tissue- and developmentally- specific multiprotein transacting factor complex, the human stage selector protein (SSP), which facilitates the interaction of the g-globin gene promoters with the upstream locus control region enhancer in fetal erythoid cells. This complex interacts with the stage selector element (SSE) in the proximal g-globin promoter, a regulatory motif phylogenetically conserved in primate species with a distinct fetal stage of β-globin like gene expression. Given these observations, we hypothesized that a similar complex modulates γ-globin in the rhesus macaque, a non-human primate model that has been utilized to study β-globin like gene expression. We focused our efforts on NF-E4, given that a human isoform of this factor confers erythroid and fetal specificity to the SSP complex. Fetal liver erythroblasts were obtained from rhesus embryos and analyzed by reverse transcriptase(RT)-PCR analysis for NF-E4 expression. NF-E4 like transcripts were identified in day 60, 80 and 120 embryonic erythroblasts, but not other rhesus tissues, demonstrating an erythroid-specific pattern of expression. Utilizing 5′ RACE, we cloned a full length NF-E4 transcript, identifying an open reading frame encoding a 131 amino acid polypeptide. This 20kD polypeptide shares a high degree of homology with human NF-E4, especially in its carboxy-terminal domain. Like human NF-E4, GST pulldown chromatography confirmed the ability of the rhesus factor to interact directly with CP2 and ALY, the other core components of the SSP. To evaluate rNF-E4 function in vivo, we utilized retrovirally mediated gene transfer to enforce expression of this factor in K562 cells, a model of human fetal erythropoiesis. Initial co-immunoprecipitation studies confirmed the in vivo interaction of rNF-E4 with other components of the SSP. Interestingly, we observed a specific 3-fold induction of γ-globin gene expression in rNF-E4 expressing cells when compared to controls. Moreover, we demonstrated that, like enforced expression of human NF-E4, rNF-E4 induced a significant increase in ε-globin gene expression. Taken together, our results suggest a conservation of NF-E4 expression and function in species with a fetal stage of globin gene expression. Moreover, the identification of rNF-E4 provides a platform for the pre-clinical development of therapeutic agents that induce high levels of NF-E4 in adult erythroblasts.

Novel Murine Model To Study Modulation of Genes and Molecular Pathways Induced Following In Vivo Interaction between Multiple Myeloma Cells and Human BM Milieu.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3409-3409
Author(s):  
Paola Neri ◽  
Pierfrancesco Tassone ◽  
Masood Shammas ◽  
Mariateresa Fulciniti ◽  
Yu-Tzu Tai ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Growth ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Murine Model ◽  
Cell Signalling

Abstract Interaction between multiple myeloma (MM) cells and the bone marrow (BM) microenvironment plays a critical role in promoting MM cell growth, survival, migration and development of drug resistance. This interaction within the bone marrow milieu is unique and its understanding is important in evaluating effects of novel agents in vitro and in vivo. We here describe a novel murine model that allows us to study the expression changes in vivo in MM cells within the human BM milieu. In this model, the green fluorescent protein (INA-6 GFP+) transduced IL-6-dependent human MM cell line, INA-6, was injected in human bone chip implanted into SCID mice. At different time points the bone chip was retrieved, cells flushed out and GFP+ MM cells were purified by CD138 MACS microbeads. Similar isolation process was used on INA-6 GFP+ cells cultured in vitro and used as control. Total RNA was isolated from these cells and gene expression profile analyzed using the HG-U133 array chip (Affymetrix) and DChip analyzer program. We have identified significant changes in expression of several genes following in vivo interaction between INA-6 and the BM microenvironment. Specifically, we observed up-regulation of genes associated with cytokines (IL-4, IL-8, IGFB 2–5) and chemokines (CCL2, 5, 6, 18, 24, CCR1, 2, 4), implicated in cell-cell signalling. Moreover genes implicated in DNA transcription (V-Fos, V-Jun, V-kit), adhesion (Integrin alpha 2b, 7, cadherin 1 and 11) and cell growth (CDC14, Cyclin G2, ADRA1A) were also up-regulated and genes involved in apoptosis and cell death (p-57, BCL2, TNF1a) were down-regulated. Using the Ingenuity Pathway Analysis the most relevant pathways modulated by the in vivo interaction between MM cells and BMSCs were IL-6, IGF1, TGF-beta and ERK/MAPK-mediated pathways as well as cell-cycle regulation and chemokine signalling. These results are consistent with previously observed in vitro cell signalling studies. Taken together these results highlight the ability of BM microenvironment to modulate the gene expression profile of the MM cells and our ability to in vivo monitor the changes. This model thus provides us with an ability to study in vivo effects of novel agents on expression profile of MM cells in BM milieu, to pre-clinically characterize their activity.

Novel In Vivo Model of Multiple Myeloma Bone Disease Using ß-Tricalcium Phosphate Artificial Bone Grafts

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4200-4200
Author(s):  
Miroslav Koulnis ◽  
Homare Eda ◽  
Loredana Santo ◽  
Ka Tat Siu ◽  
Janani Ramachandran ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Tumor Growth ◽  
Bone Graft ◽  
Bone Disease ◽  
Tricalcium Phosphate ◽  
Research Funding ◽  
Bone Graft Substitute ◽  
Artificial Bone ◽  
Fetal Bone

Abstract Model systems to study Multiple Myeloma (MM) related bone disease exist but have a number of limitations. Disseminated MM models have variable cell homing and do not precisely recapitulate the human microenvironment interactions with myeloma cells. Severe combined immunodeficiency (SCID) mice engrafted with human fetal bone (SCID-hu) have been used by us, and are able to recapitulate the human bone marrow microenvironment. The fetal bone chips are however difficult to obtain, and vary in size and shape, complicating inter-sample comparison. Similarly, the poly-ε-caprolactone polymeric scaffold, previously used to seed murine or human stromal compartment, may not correctly reproduce bone destruction and inhibition of osteogenesis by MM as seen in patients, making this model difficult to test therapies targeting the MM niche. β-tricalcium phosphate (β-TCP) is a biocompatible and biodegradable bone graft substitute that is uniform in structure and easily available, and may be a viable alternative to overcome SCID-hu difficulties in modeling MM bone disease. Here, we utilized β-TCP bone graft substitute to develop a novel in vivo MM model where β-TCP permits the development of the bone microenvironment, supports MM development, and is technically feasible and highly reproducible. Using this model, we aim to better understand the biology of the niche in MM by genetically modifying its components and by testing new niche-targeting therapies. Our initial results show that osteogenesis takes place in the β-TCP bone graft, and the implant is supportive of MM tumor growth. Inter-scapular subcutaneous implantation of β-TCP alone, or co-implantation with human-derived stromal cell line HS27A in immunocompromised recipients resulted in the expression of osteogenic markers Runx2, alkaline phosphatase (ALP), Col1A1, and Osteocalcin (OCN), as well as a marker of bone resorption. Further, implants supported the growth of human-derived MM1.S and murine 5TGM1 cells, as visualized directly in vivo by serial luciferase bioluminescence imaging (BLI) and by immunohistochemistry. Modifying the niche compartment in Cre/iDTR animals with MM disease is an exciting novel strategy to understand which niche component in vivo may be targeted to suppress MM development. Mouse strains with promoter-specific Cre recombinase that induces the expression of the diphtheria toxin (DT) receptor (iDTR) can be utilized to selectively ablate a cell population of interest in vivo, via intraperitoneal DT injection. Here, we first utilized OCN-Cre/iDTR mice to test the deletion of mature osteoblasts in β-TCP artificial bone graft post-implantation. Our data show a dose-dependent reduction in osteoblastic markers OCN, ALP, Runx2, Sclerostin, Osteoprotegerin and RANKL. Importantly, DT ablation of osteoblasts in the β-TCP implant resulted in a significantly increased 5TGM1 tumor growth, as judged by BLI and tumor weight. Our data show that the mature osteocalcin-positive niche population is protective against MM disease. Ongoing studies of the β-TCP mouse model will address the relative contribution of various osteogenic populations to the course of MM development in vivo, and test the efficacy of novel MM drugs. Disclosures Raje: BMS: Consultancy; Amgen: Consultancy; Celgene Corporation: Consultancy; Takeda: Consultancy; Onyx: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Onyx: Consultancy; BMS: Consultancy; AstraZeneca: Research Funding; Eli Lilly: Research Funding; AstraZeneca: Research Funding; Millenium: Consultancy; Eli Lilly: Research Funding; Novartis: Consultancy; Acetylon: Research Funding; Millenium: Consultancy; Novartis: Consultancy; Acetylon: Research Funding.

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