Cancer Research Highlights: Researchers Develop "Knock-In" Mouse Model of Plasma Cell Cancers

2004 ◽  
Author(s):  
Keyword(s):  
Cancer Research ◽  
Mouse Model ◽  
Plasma Cell

scholarly journals An Inducible, Large-Intestine-Specific Transgenic Mouse Model for Colitis and Colitis-Induced Colon Cancer Research

2015 ◽  
Vol 61 (4) ◽  
pp. 1069-1079 ◽  
Author(s):  
Fa Wang ◽  
Robert L. Johnson ◽  
Paul W. Snyder ◽  
Marsha L. DeSmet ◽  
James C. Fleet
Keyword(s):  
Colon Cancer ◽  
Cancer Research ◽  
Mouse Model ◽  
Transgenic Mouse ◽  
Large Intestine ◽  
Transgenic Mouse Model

Mouse Model of MYC-Deregulating Chromosomal Translocations Associated with Human Burkitt Lymphoma and Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2832-2832
Author(s):  
Siegfried Janz ◽  
Shaughnessy D. John
Keyword(s):  
Multiple Myeloma ◽  
Mouse Model ◽  
Plasma Cell ◽  
Heavy Chain ◽  
Burkitt Lymphoma ◽  
Immunoglobulin Heavy Chain ◽  
Mrna Levels ◽  
Gene Insertion ◽  
Chain Locus ◽  
Heavy Chain Locus

Abstract Purpose: Burkitt lymphoma (BL) is tightly associated with chromosomal t(8;14)(q24;q32) translocations that result in the deregulated expression of the MYC (c-myc) oncogene due to its juxtaposition to enhancers of the immunoglobulin-heavy chain locus IGH. The t(8;14)(q24;q32) MYC-IGH translocation is widely believed to be the initiating event in the pathogenesis of BL. Multiple myeloma (MM) is a malignant neoplasm of plasma cells that is often associated with complex cytogenetic alterations that juxtapose MYC, analogous to the t(8;14)(q24;q32) translocation, to IGH enhancers. However, MYC-IGH rearrangements of this sort occur during the progression of MM, not as tumor-initiating events as in BL. Accurate mouse models of MYC deregulation associated with human BL and MM are needed to study the events involved in tumor initiation and progression and design new approaches for treatment and prevention. To that end, we have generated a new mouse model of human t(8;14)(q24;q32) translocation. Experimental procedure: We inserted a His6-tagged mouse Myc cDNA, MycHis, into two different locations of the mouse immunoglobulin heavy-chain locus, Igh, just 5′ of Eμ or Cμ. In the latter case, Eμ was deleted during gene targeting. The newly developed gene-insertion strains were designated iMycEμ and iMycCμ. The iMycEμ mice provide a specific model of the t(8;14)(q24;q32) observed in endemic BL (eBL). The iMycCμ mice mimic the t(8;14)(q24;q32) found in sporadic BL (sBL) and immunodeficiency-associated BL (iBL) (Fig. 1). Figure 1 Figure 1. Result: Both “iMyc” gene-insertion strains are prone to the spontaneous development of mature B cell and plasma cell tumors. However, in the Eμ-containing iMycEμ mice, tumors arose earlier and tumor incidence was higher compared to the Eμ-deleted iMycCμ (Fig. 2 left). Figure 2 Figure 2. This correlated well with the control of MycHis expression by Eμ, as MycHis mRNA levels were higher in B cells from iMycEμ than iMycCμ mice. Interestingly, the iMycCμ transgene was as effective in inducing inflammation-dependent peritoneal plasmacytomas as the iMycCμ transgene (Fig. 2 right). This indicated that host factors, such as chronic inflammation, can greatly enhance the transformation-inducing potency of a deregulated Myc gene that is only weakly oncogenic in spontaneous tumor development. Conclusion: The “iMyc” mice provide a model of Myc deregulation that is conducive to plasma cell tumors in mice. The mice may thus afford a good opportunity to identify the genes that collaborate with Myc in neoplastic plasma cell development. Combined with the transgenic expression of MM genes, such as DKK1, the “iMyc” mice may also be useful as a platform for modelling human plasma cell neoplasms in mice.

Evaluating the Antitumor Activity of MLN9708 in a Disseminated Mouse Model of Double Transgenic iMyc Ca/Bcl-XL Plasma Cell Malignancy.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3835-3835 ◽  
Author(s):  
Michael Fitzgerald ◽  
Yueying Cao ◽  
Bret Bannerman ◽  
Zhi Li ◽  
Olga Tayber ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Mouse Model ◽  
Lymph Nodes ◽  
Plasma Cell ◽  
Research Funding ◽  
Ex Vivo ◽  
Employment Equity ◽  
Equity Ownership

Abstract Abstract 3835 Poster Board III-771 Introduction The first generation proteasome inhibitor VELCADE® (bortezomib) is indicated for the treatment of patients with multiple myeloma (MM), a form of plasma cell malignancy (PCM). MLN9708 is our novel proteasome inhibitor that selectively and reversibly binds to, and potently inhibits the b5 site of the 20s proteasome in preclinical studies. We have recently demonstrated that MLN9708 significantly prolongs tumor-free survival of double transgenic iMycCa/Bcl-XL mice, a genetically-engineered mouse model of de novo PCM. Here we describe the in vivo evaluation of cell lines derived from double transgenic iMycCa/Bcl-XL mice and the antitumor activity of MLN9708 in a disseminated mouse model of iMycCa/Bcl-XL PCM. Materials MLN9708 immediately hydrolyzes to MLN2238, the biologically active form, upon exposure to aqueous solutions or plasma. MLN2238 was used for all preclinical studies described below. Double transgenic iMycCa/Bcl-XL mice develop de novo PCM, in which neoplastic plasma cell development is driven by the targeted expression of the oncoprotein Myc and anti-apoptotic Bcl-XL (J. Clin. Invest. 113:1763-1773, 2004). DP54 and DP42 are plasma cell tumor cell lines isolated from the bone marrow and lymph nodes, respectively, of syngeneic mice previously inoculated with iMycCa/Bcl-XL tumors (Cancer Res. 67:4069-4078, 2007). In vitro, DP54 and DP42 cells express both the Myc and Bcl-XL transgenes, various plasma cell and B-cell markers including CD38, CD138 and B220, and have gene expression profiles very similar to human MM. Methods Cell viability studies were performed to determine the antiproliferative effects of MLN2238 in DP54 and DP42 cells in vitro. To evaluate DP54 and DP42 cells in vivo, these cells were aseptically inoculated into the tail vein of NOD-SCID mice. Progressions of the resultant PCM were monitored and tumor burdens were evaluated by magnetic resonance imaging (MRI), ex vivo mCT imaging, and histopathology. Mouse plasma samples were collected at the end of the studies and levels of immunoglobulin were assessed. To establish a preclinical disseminated mouse model of iMycCa/Bcl-XL PCM, freshly dissociated DP54-Luc cells (constitutively expressing firefly luciferase under a mouse Ig-k promoter) were aseptically inoculated into the tail vein of NOD-SCID mice. Once tumor growth has been established, mice were randomized into treatment groups and then treated with vehicle, bortezomib (at 0.7mg/kg intravenously [IV] twice weekly [BIW]) or MLN2238 (at 11 mg/kg IV BIW) for 3 consecutive weeks. Tumor burden was measured by bioluminescent imaging. Results In vitro, both DP54 and DP42 cells were sensitive to MLN2238 treatment (LD50 values of 14 and 25 nM, respectively). In vivo, NOD-SCID mice rapidly succumbed to PCM after being inoculated with DP54 and DP42 cells (25 and 14 days post-inoculation, respectively), where the disease was accompanied by marked elevation of plasma immunoglobulins. MRI scans revealed the presence of multiple lesions and several abnormalities were found including: cranial deformation, bowel distortion, splenomegaly and renal edema. Tumor infiltrates, ranging from minor to extensive, were identified in multiple organ compartments (brain<kidney<liver<lymph nodes<spleen<bone marrow) by histopathological analysis. Ex vivo mCT imaging has also revealed signs of bone erosion in the cranial sagittal sutures. Dissemination of DP54-Luc cells after tail vein inoculations was detected by in vivo bioluminescent and confirmed by ex vivo imaging where luminescent tumor nodules were identified in the spleen, kidneys, liver, intestine, lymph nodes, spinal bone and cranium. To assess the antitumor activity of MLN2238, an efficacy study was performed using the DP54-Luc disseminated model. Tumor burden (bioluminescence), skeletal malformation (mCT) and overall survival after treatment with bortezomib and MLN2238 will be presented. Conclusion The DP54-Luc disseminated mouse model of double transgenic iMycCa/Bcl-XL PCM recapitulated several key features of human MM and provided real-time assessment of novel MM therapy preclinically. MLN9708 is currently in human clinical development for both hematological and solid tumor indications. Disclosures: Cao: Milllennium: Employment, Equity Ownership. Bannerman:Milllennium: Employment. Li:Milllennium: Employment. Bradley:Milllennium: Employment, Equity Ownership, Research Funding. Silverman:Milllennium: Employment. Janz:Milllennium: Research Funding. Van Ness:Milllennium: Research Funding. Kupperman:Milllennium: Employment. Manfredi:Milllennium: Employment. Lee:Milllennium: Employment, Equity Ownership.

Constitutive gp130-JAK-STAT3 Signaling Induces a Plasma Cell Disorder Representing Genetic and Clinical Features of Human Myeloma – a Novel in Vivo Model for the Patient Subgroup Characterized By a STAT3 Target Gene Signature

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 648-648
Author(s):  
Sabine Steidle ◽  
Tobias Dechow ◽  
Katharina Götze ◽  
Martina Rudelius ◽  
Konstanze Pechloff ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mouse Model ◽  
Plasma Cell ◽  
Monoclonal Gammopathy ◽  
Bone Lesions ◽  
Activation Pattern ◽  
Stat3 Pathway ◽  
Pathway Activation ◽  
Lytic Bone Lesions

Abstract Multiple myeloma (MM) is a plasma cell neoplasm characterized by the clonal expansion of an immunoglobulin-secreting terminally differentiated B cell. MM patients classically suffer from the triade consisting of plasma cell infiltration of the bone marrow, lytic bone lesions and monoclonal gammopathy in plasma and/or urine. During disease progress patients develop end organ damage such as nephropathy, neuropathy and bone marrow insufficiency. New treatment options including immunomodulatory drugs and proteasome inhibitors have prolonged overall survival and quality of life. However MM is still considered an incurable disease by conventional treatment approaches. Deregulated signal transduction pathways, in particular the Interleukin-6-JAK-STAT3 pathway, play an important role in the growth regulation and survival of MM cells. IL-6 binds to the specific IL-6 receptor and this complex associates with two molecules of the ubiquitously expressed common signal transducer gp130, which leads to JAK-STAT3 activation and STAT3 target expression. Using immunohistochemistry for STAT3 phosphorylation and by assessing gene expression data we have identified a recurrent STAT3 pathway activation pattern in approximately 40% of all MM patients, strongly indicating that deregulated gp130 downstream activation constitutes an attractive therapeutic target in MM. Based on these findings we generated a novel retroviral bone marrow transduction-transplantation MM mouse model using a constitutively active form of gp130, L-gp130. This L-gp130 mouse model shows all characteristics of the human disease, including monoclonal gammopathy, bone marrow infiltration with lytic bone lesions, and protein deposition in the kidney. Essentially, as compared to previous MM models, MM penetrance is very high and tumor latency with a median of approximately 200 days short. The disease is easily transplantable into secondary recipient mice. To assess clonality we subcloned and sequenced IgH rearrangements from individual tumors. Our analyses revealed that diseased mice contained monoclonal and oligoclonal B cell expansions, and also demonstrated a germinal center passage. Fluorescence in situ hybridization revealed the occurrence of Myc aberrations, a genetic feature that is associated with aggressive disease and short survival in human MM. A genetic in vivo approach revealed that gp130 signaling collaborates with Myc to induce MM, and that gp130 signaling is responsible and sufficient for directing the plasma cell phenotype and to dominantly regulate the expression of antiapoptotic proteins. Finally, testing of murine primary MM cells isolated from diseased L-gp130 animals with currently used anti-myeloma drugs such as bortezomib, carfilzomib, melphalan and doxorubicin revealed significant anti-tumor activity. In summary, the L-gp130 MM mouse model provides a novel tool with clinical and genetic features of human MM. It offers several clear advantages over existing murine MM models. Regarding the patient subgroup with a recurrent STAT3 pathway activation pattern it may serve as a genetic and preclinical tool for delineating MM pathogenesis, for evaluation of targeted therapies, and for assessment of in vivo treatment resistance. Disclosures Keller: Cellgene: Research Funding.

Expression of Germinal Center B Cell Markers in Bortezomib-Resistant Multiple Myeloma Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 129-129 ◽  
Author(s):  
Holly Stessman ◽  
Linda B. Baughn ◽  
Aatif Mansoor ◽  
Brian Van Ness
Keyword(s):  
Multiple Myeloma ◽  
Cell Differentiation ◽  
Mouse Model ◽  
B Cell ◽  
Plasma Cell ◽  
Germinal Center ◽  
Research Funding ◽  
B Cell Differentiation ◽  
Cell Markers ◽  
Resistant Lines

Abstract Abstract 129 Multiple myeloma (MM), the second most common hematopoietic malignancy, is an incurable plasma cell neoplasm representing approximately 2% of all cancer deaths. The proteasome inhibitor, bortezomib (Bz), has been widely used to treat MM, and emerging next-generation proteasome inhibitors are being evaluated. Despite advances in therapies, patients treated with Bz eventually relapse due to the development of drug resistance. Thus, identifying signatures that distinguish Bz sensitive from resistant MM cells will more accurately predict Bz sensitivity and will aid in the development of novel approaches to reverse resistance. MM populations are characterized by phenotypic heterogeneity suggesting the possibility that certain MM subpopulations are associated with Bz resistance. In order to characterize these populations in greater detail, we have utilized isogenic pairs of Bz sensitive and resistant MM lines derived from the genetically engineered iMycCa/Bcl-xl mouse model of plasma cell malignancy. The iMycCa/Bcl-xl mouse is a highly robust model that very closely resembles human MM based on gene expression profiling (GEP), chromosomal abnormalities and progression of disease and response to therapy (Boylan, et al. Cancer Res (2007) 67: 4069). We have employed this mouse model because of its striking similarity to human MM, and MM cells isolated from these mice can be readily infected by lentivirus as well as adoptively transferred into syngeneic, immunocompetent recipients establishing a powerful system to directly test biologically relevant hypotheses relating to Bz resistance. Isogenic pairs of Bz sensitive and resistant lines were extensively characterized using GEP, quantitative PCR and flow cytometry. We observed increased expression of germinal B cell markers Pax5, AID and Bcl-6 and reduced expression of the plasma cell marker CD93 in Bz resistant lines compared to Bz sensitive pairs suggesting that Bz resistance is associated with germinal center-like B cell characteristics. Remarkably, we detect within the same cell co-expression of both CD138/Pax5 and CD138/AID demonstrating the tremendous plasticity of these cells and their intermediate B cell differentiation phenotype. Recently, both AID and Bcl-6 have been identified as crucial mediators of resistance to tyrosine kinase inhibitors in leukemia cells (Duy, et al. Nature (2011) 473: 384; Klemm, et al. Cancer Cell (2009) 16: 232) raising an intriguing possibility that these proteins thought to be restricted to germinal center B cells could play a role in Bz resistance in MM. These observations have led us to more closely characterize the apparent shift in developmental stage resulting from Bz-driven expression changes or selection. Time course analysis of gene and protein expression following low-dose Bz treatment in the absence of cell death indicates that Bz increases the expression and promotes the stabilization of Pax5, AID and Bcl-6. This demonstrates a drug-induced change in markers associated with B cell differentiation relating to the ultimate emergence of the resistance phenotype. We are now determining whether similar B cell differentiation phenotypes emerge in a recently published human drug trial where GEP was completed prior to and 48 hours after Bz treatment in patients (Shaughnessy, et al. Blood (2011), ahead of print). Thus, we will present phenotypic signatures correlating to Bz resistance in cell lines derived from our mouse model of MM and suggest that targeting B cell differentiation may represent a rational therapeutic approach to overcoming Bz resistance. Disclosures: Stessman: Millennium: The Takeda Oncology Company: Research Funding. Mansoor:Millennium: The Takeda Oncology Company: Research Funding. Van Ness:Millennium: The Takeda Oncology Company: Research Funding.

scholarly journals Utx Insufficiency Cooperates with Braf V600E in the Induction of Myeloma in Mice

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1005-1005
Author(s):  
Ola Rizq ◽  
Naoya Mimura ◽  
Motohiko Oshima ◽  
Shuji Momose ◽  
Yaeko Nakajima-Takagi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Mouse Model ◽  
Plasma Cell ◽  
High Frequency ◽  
Research Funding ◽  
Plasma Cells ◽  
Braf V600e ◽  
Gene Sets ◽  
Plasma Cell Neoplasms

Abstract Introduction: Dysfunction of epigenetic pathways has been frequently implicated in hematological malignancies. In multiple myeloma (MM), EZH2, a methyltransferase that induces histone H3 lysine 27 trimethylation (H3K27me3), acts as an oncogene as evidenced by its overexpression, which was found to be positively correlated with disease progression (Kalushkova et al. PloS One. 2010). We have shown that inhibition of both EZH2 and its homolog EZH1 is effective in eradicating MM cells in vitro and in vivo (Rizq et al. Clin Cancer Res. 2017). In addition, inactivating somatic mutations in UTX/KDM6A, an X-linked histone demethylase that removes di- and tri-methyl groups from H3K27, are found in 3 - 10% of MM patients (van Haaften et al. Nat Genet. 2009 and Pawlyn et al. Clin Cancer Res. 2016), indicating a tumor suppressive role for UTX, which has yet to be delineated. Up till now, no mouse model has been generated to test Utx insufficiency in post germinal center (GC) B cells and plasma cells. On the other hand, an activating mutation V600E in the BRAF kinase gene is closely associated with aggressive disease features such as extramedullary disease and shorter overall survival in MM patients (Andrulis et al. Cancer Discov. 2013) and could accelerate induction of myeloma in mice. Methods: To investigate whether loss of Utx cooperates with Braf V600E in myelomagenesis in mice, we generated and analyzed mice with conditional knock-out allele of Utx and/or knock-in allele of Braf V600E combined with Cγ1-Cre allele, in which Cre is activated by immunization in post GC B cells. Results: Loss of Utx and Braf V600E synergistically induced post GC B-cell lymphoma and plasma cell neoplasms in mice and significantly shortened the survival of mice compared with control mice and either allele alone. Utx-/-Braf V600E females succumbed to death earlier than Utx-/YBraf V600Emales and Utx-/+Braf V600Efemales. Of note, plasma cell neoplasms developed at a high frequency in Utx-/YBraf V600Emales and Utx-/+Braf V600Efemales and, less frequently, in Utx-/-Braf V600E females. Mice with plasma cell neoplasms showed expansion of CD138+ plasma cells in bone marrow as well as spleen and/or lymph nodes, exhibiting extramedullary disease. Loss of Utx alleles and expression of Braf V600E were confirmed by genomic PCR of plasma cells. Importantly, the clonality of plasma cells was demonstrated by genomic PCR detecting rearrangements of immunoglobulin heavy and light chain genes. In addition, M protein was detected by serum protein electrophoresis (SPEP) at a high frequency. Notably, we were able to establish murine myeloma cell lines from moribund compound mice. These cells readily engrafted in the bone marrow of NOG mice after transplantation and caused myeloma-associated phenotypes including paraplegia in recipient mice. Interestingly, Utx-/-Braf V600E cells were sensitive to dual inhibition of EZH2 and EZH1 but not to specific inhibition of EZH2 in culture. They also showed decreased susceptibility to proteasome inhibitors when compared with human MM cell lines. To gain insight into the changes in the transcriptional landscape following Utx loss, we performed RNA sequencing (RNA seq) and then gene set enrichment analysis (GSEA). We found positive enrichment of gene sets related to Myc, implying that Myc is one of the main drivers of myelomagenesis in our mouse model. In addition, gene sets related to MM were significantly enriched following Utx loss. We are now working on ChIP sequencing (ChIP seq) of UTX-related histone modifications to evaluate the epigenetic impact of Utx loss on myelomagenesis. Conclusion: Utx insufficiency cooperates with Braf V600E in the induction of myeloma in mice. Our mouse model is a promising tool for understanding the role of epigenetic dysregulation in the pathogenesis of MM and evaluating novel anti-myeloma agents. Disclosures Okuno: Celgene: Research Funding. Tamaru:Nichirei Bioscience INC.: Research Funding; Takeda Pharmaceutical Company Limited: Speakers Bureau.

The Novel Proteasome Inhibitor MLN9708 Demonstrates Efficacy in a Genetically-Engineered Mouse Model of DeNovo Plasma Cell Malignancy.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3849-3849 ◽  
Author(s):  
Siegfried Janz ◽  
Brian G Van Ness ◽  
Vishala Neppalli ◽  
Ray Liu ◽  
Michael D Pickard ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Mouse Model ◽  
Plasma Cell ◽  
Proteasome Inhibitor ◽  
Genetically Engineered ◽  
Employment Equity ◽  
Osteolytic Lesions ◽  
Free Survival ◽  
Genetically Engineered Mouse Model ◽  
Equity Ownership

Abstract Abstract 3849 Poster Board III-785 Introduction The first-in-class proteasome inhibitor VELCADË (bortezomib) is a critical component of chemotherapeutic strategy in treating multiple myeloma (MM), a plasma cell malignancy characterized by monoclonal gammopathy and osteolytic lesions. However, patients eventually develop bortezomib resistance, highlighting the continuous challenge to further improve myeloma therapy. We have recently identified a novel proteasome inhibitor MLN9708 that shows greater antitumor activity than bortezomib in a number of preclinical xenograft models. Here we describe antitumor activity of MLN9708 in a genetically engineered mouse model of human MM. In this model, neoplastic plasma cell development is driven by deregulated expression of Myc (c-myc, myelocytomatosis oncogene) and Bcl-x (official gene name: Bcl2l1; encodes the anti-apoptotic Bcl-XL oncoprotein). This is the first preclinical in vivo study of proteasome inhibitors employing a transgenic mouse model of human MM in which plasma cell neoplasms develop de novo. Materials Upon exposure to aqueous solutions or plasma, MLN9708 immediately hydrolyzes to MLN2238, the biologically active form. MLN2238 was used for all preclinical studies described below. Methods We have previously demonstrated that intercrossing C57BL/6 mice carrying the iMycCa transgene (insertion of Myc in the immunoglobulin heavy-chain locus, Igh) with FVB/N mice carrying the 3'KE-Bcl-XL transgene (enforced expression of Bcl-x driven by the immunoglobulin light-chain 3' k enhancer and Vk21 promoter) produces double transgenic F1 hybrid iMycCa/Bcl-XL mice that develop plasma cell malignances with short onset (135 days on average) and full penetrance (100% tumor incidence; J. Clin. Invest. 113:1763-1773, 2004). These double transgenic iMycCa/Bcl-XL mice develop hypergammaglobulinemia and tissue plasmacytosis by 6-8 weeks of age and rapidly succumb to malignant plasma cell tumors by less than 200 days of age. Preliminary studies based on 11 tumor-bearing iMycCa/Bcl-XL mice showed this form of plasma cell malignancy recapitulates important features of human MM, including serum paraproteins, infiltration of bone marrow with malignant plasma cells, osteolytic lesions and myeloma-like global gene expression profiles (Cancer Res. 67:4069-4078, 2007). Here we used the iMycCa/Bcl-XL mouse model of human MM to assess the antitumor activity of bortezomib and MLN9708 in a preclinical setting. Results Untreated double transgenic iMycCa/Bcl-XL mice (n=30) invariably developed plasma cell tumors with short onset (median tumor-free survival = 112 days) and showed marked elevations in plasma immunoglobulin IgM, IgG1, IgG2a and IgG2b levels. To assess antitumor activity of bortezomib and MLN2238, 9-week-old iMycCa/Bcl-XL mice were treated intravenously (IV) twice per week (BIW) with bortezomib (1.2 mg/kg) or MLN2238 (18 mg/kg) for 6 consecutive weeks. These doses represent the maximum tolerated dose (MTD) for each drug as previously determined in normal C57BL/6 x FVB/N F1 hybrid mice. Treatment of iMycCa/Bcl-XL mice with bortezomib (n=30) significantly prolonged tumor-free survival compared to untreated controls (median tumor-fee survival = 139 days; hazard ratio = 0.116; 95% CI = 0.057 to 0.235; p<0.0001). Importantly, treatment of iMycCa/Bcl-XL mice with MLN2238 (n=30) also significantly prolonged tumor-free survival relative to untreated controls (median tumor-free survival = 148 days; hazard ratio = 0.144; 95% CI = 0.071 to 0.289; p<0.0001). Immunoglobulin levels, overall tumor burden, osteolytic lesions (mCT) and biochemical parameters of myeloma bone disease after treatment with bortezomib and MLN2238 will be presented. Conclusion The novel proteasome inhibitor MLN9708 demonstrates striking antitumor activity in a genetically engineered mouse model of human MM, significantly prolonging tumor-free survival of double transgenic iMycCa/Bcl-XL mice. MLN9708 is currently in human clinical development for both hematological and solid tumor indications. Disclosures: Janz: Millennium – The Takeda Oncology Company: Research Funding. Van Ness:Millennium: Research Funding; Scientific Advisory Board, International Myeloma Foundation: Membership on an entity's Board of Directors or advisory committees. Liu:Milllennium: Employment, Equity Ownership. Pickard:Milllennium: Employment. Terkelsen:Milllennium: Employment. Bradley:Milllennium: Employment, Equity Ownership, Research Funding. Kupperman:Milllennium: Employment. Manfredi:Milllennium: Employment. Lee:Milllennium: Employment, Equity Ownership.

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