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3. A niche-dependent myeloid transcriptome signature defines dormant myeloma cells

Author

Khoo, Weng Hua, Ledergor, Guy, Weiner, Assaf, Roden, Daniel L., Terry, Rachael L., McDonald, Michelle M., Chai, Ryan C., De Veirman, Kim, Owen, Katie L., Opperman, Khatora S., Vandyke, Kate, Clark, Justine R., Seckinger, Anja, Kovacic, Natasa, Nguyen, Akira, Mohanty, Sindhu T., Pettitt, Jessica A., Xiao, Ya, Corr, Alexander P., Seeliger, Christine, Novotny, Mark, Lasken, Roger S., Nguyen, Tuan V., Oyajobi, Babatunde O., Aftab, Dana, Swarbrick, Alexander, Parker, Belinda, Hewett, Duncan R., Hose, Dirk, Vanderkerken, Karin, Zannettino, Andrew C.W., Amit, Ido, Phan, Tri Giang, and Croucher, Peter I.

Published
2019
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4. Myeloperoxidase creates a permissive microenvironmental niche for the progression of multiple myeloma

Author

Williams, Connor M. D., primary, Noll, Jacqueline E., additional, Bradey, Alanah L., additional, Duggan, Jvaughn, additional, Wilczek, Vicki J., additional, Masavuli, Makutiro G., additional, Grubor‐Bauk, Branka, additional, Panagopoulos, Romana A., additional, Hewett, Duncan R., additional, Mrozik, Krzysztof M., additional, Zannettino, Andrew C. W., additional, Vandyke, Kate, additional, and Panagopoulos, Vasilios, additional

Published
2023
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7. Supplementary Data from HIF-2α Promotes Dissemination of Plasma Cells in Multiple Myeloma by Regulating CXCL12/CXCR4 and CCR1

Author

Vandyke, Kate, primary, Zeissig, Mara N., primary, Hewett, Duncan R., primary, Martin, Sally K., primary, Mrozik, Krzysztof M., primary, Cheong, Chee Man, primary, Diamond, Peter, primary, To, L. Bik, primary, Gronthos, Stan, primary, Peet, Daniel J., primary, Croucher, Peter I., primary, and Zannettino, Andrew C.W., primary

Published
2023
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8. Supp Figure 4 from HIF-2α Promotes Dissemination of Plasma Cells in Multiple Myeloma by Regulating CXCL12/CXCR4 and CCR1

Author

Vandyke, Kate, primary, Zeissig, Mara N., primary, Hewett, Duncan R., primary, Martin, Sally K., primary, Mrozik, Krzysztof M., primary, Cheong, Chee Man, primary, Diamond, Peter, primary, To, L. Bik, primary, Gronthos, Stan, primary, Peet, Daniel J., primary, Croucher, Peter I., primary, and Zannettino, Andrew C.W., primary

Published
2023
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10. Supplementary Table 1 from HIF-2α Promotes Dissemination of Plasma Cells in Multiple Myeloma by Regulating CXCL12/CXCR4 and CCR1

Author

Vandyke, Kate, primary, Zeissig, Mara N., primary, Hewett, Duncan R., primary, Martin, Sally K., primary, Mrozik, Krzysztof M., primary, Cheong, Chee Man, primary, Diamond, Peter, primary, To, L. Bik, primary, Gronthos, Stan, primary, Peet, Daniel J., primary, Croucher, Peter I., primary, and Zannettino, Andrew C.W., primary

Published
2023
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11. Supp Figure 3 from HIF-2α Promotes Dissemination of Plasma Cells in Multiple Myeloma by Regulating CXCL12/CXCR4 and CCR1

Author

Vandyke, Kate, primary, Zeissig, Mara N., primary, Hewett, Duncan R., primary, Martin, Sally K., primary, Mrozik, Krzysztof M., primary, Cheong, Chee Man, primary, Diamond, Peter, primary, To, L. Bik, primary, Gronthos, Stan, primary, Peet, Daniel J., primary, Croucher, Peter I., primary, and Zannettino, Andrew C.W., primary

Published
2023
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12. Supp Figure 5 from HIF-2α Promotes Dissemination of Plasma Cells in Multiple Myeloma by Regulating CXCL12/CXCR4 and CCR1

Author

Vandyke, Kate, primary, Zeissig, Mara N., primary, Hewett, Duncan R., primary, Martin, Sally K., primary, Mrozik, Krzysztof M., primary, Cheong, Chee Man, primary, Diamond, Peter, primary, To, L. Bik, primary, Gronthos, Stan, primary, Peet, Daniel J., primary, Croucher, Peter I., primary, and Zannettino, Andrew C.W., primary

Published
2023
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13. Supp Figure 2 from HIF-2α Promotes Dissemination of Plasma Cells in Multiple Myeloma by Regulating CXCL12/CXCR4 and CCR1

Author

Vandyke, Kate, primary, Zeissig, Mara N., primary, Hewett, Duncan R., primary, Martin, Sally K., primary, Mrozik, Krzysztof M., primary, Cheong, Chee Man, primary, Diamond, Peter, primary, To, L. Bik, primary, Gronthos, Stan, primary, Peet, Daniel J., primary, Croucher, Peter I., primary, and Zannettino, Andrew C.W., primary

Published
2023
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14. Supp Figure 1 from HIF-2α Promotes Dissemination of Plasma Cells in Multiple Myeloma by Regulating CXCL12/CXCR4 and CCR1

Author

Vandyke, Kate, primary, Zeissig, Mara N., primary, Hewett, Duncan R., primary, Martin, Sally K., primary, Mrozik, Krzysztof M., primary, Cheong, Chee Man, primary, Diamond, Peter, primary, To, L. Bik, primary, Gronthos, Stan, primary, Peet, Daniel J., primary, Croucher, Peter I., primary, and Zannettino, Andrew C.W., primary

Published
2023
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15. Supplementary Table 2 from HIF-2α Promotes Dissemination of Plasma Cells in Multiple Myeloma by Regulating CXCL12/CXCR4 and CCR1

Author

Vandyke, Kate, primary, Zeissig, Mara N., primary, Hewett, Duncan R., primary, Martin, Sally K., primary, Mrozik, Krzysztof M., primary, Cheong, Chee Man, primary, Diamond, Peter, primary, To, L. Bik, primary, Gronthos, Stan, primary, Peet, Daniel J., primary, Croucher, Peter I., primary, and Zannettino, Andrew C.W., primary

Published
2023
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19. A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q-syndrome

Author

Barlow, Jillian L., Drynan, Lesley F., Hewett, Duncan R., Holmes, Luke R., Lorenzo-Abalde, Silvia, Lane, Alison L., Jolin, Helen E., Pannell, Richard, Middleton, Angela J., Wong, See Heng, Warren, Alan J., Wainscoat, James S., Boultwood, Jacqueline, and McKenzie, Andrew N.J.

Subjects
Myelodysplastic syndromes -- Research, Bone marrow cells -- Research, Human chromosome abnormalities -- Research, Chromosome deletion -- Research, Macrocytic anemia -- Research, Biological sciences, Health
Abstract

The identification of the genes associated with chromosomal translocation breakpoints has fundamentally changed understanding of the molecular basis of hematological malignancies. By contrast, the study of chromosomal deletions has been hampered by the large number of genes deleted and the complexity of their analysis. We report the generation of a mouse model for human 5q-syndrome using large-scale chromosomal engineering. Haploinsufficiency of the Cd74-Nid67 interval (containing Rps14, encoding the ribosomal protein S14) caused macrocytic anemia, prominent erythroid dysplasia and monolobulated megakaryocytes in the bone marrow. These effects were associated with defective bone marrow progenitor development, the appearance of bone marrow cells expressing high amounts of the tumor suppressor p53 and increased bone marrow cell apoptosis. Notably, intercrossing with p53-deficient mice completely rescued the progenitor cell defect, restoring common myeloid progenitor and megakaryocytic-erythroid progenitor, granulocyte-monocyte progenitor and hematopoietic stem cell bone marrow populations. This mouse model suggests that a p53-dependent mechanism underlies the pathophysiology of the 5q-syndrome., 5q-syndrome was first described in 1974 as a consistent association of the deletion of the long arm of chromosome 5 (del(5q)) with hematological abnormalities: macrocytosis, anemia, normal or high platelet [...]

Published
2010
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22. Targeted Disruption of Bone Marrow Stromal Cell-Derived Gremlin1 Limits Multiple Myeloma Disease Progression In Vivo

Author

Clark, Kimberley C., primary, Hewett, Duncan R., additional, Panagopoulos, Vasilios, additional, Plakhova, Natalya, additional, Opperman, Khatora S., additional, Bradey, Alanah L., additional, Mrozik, Krzysztof M., additional, Vandyke, Kate, additional, Mukherjee, Siddhartha, additional, Davies, Gareth C.G., additional, Worthley, Daniel L., additional, and Zannettino, Andrew C.W., additional

Published
2020
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23. LCRF‐0006, a small molecule mimetic of the N‐cadherin antagonist peptide ADH‐1, synergistically increases multiple myeloma response to bortezomib

Author

Mrozik, Krzysztof M., primary, Cheong, Chee M., additional, Hewett, Duncan R., additional, Noll, Jacqueline E., additional, Opperman, Khatora S., additional, Adwal, Alaknanda, additional, Russell, Darryl L., additional, Blaschuk, Orest W., additional, Vandyke, Kate, additional, and Zannettino, Andrew C. W., additional

Published
2020
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24. Twist-1 is upregulated by NSD2 and contributes to tumour dissemination and an epithelial-mesenchymal transition-like gene expression signature in t(4;14)-positive multiple myeloma

Author

Cheong, Chee Man, primary, Mrozik, Krzysztof M., additional, Hewett, Duncan R., additional, Bell, Elyse, additional, Panagopoulos, Vasilios, additional, Noll, Jacqueline E., additional, Licht, Jonathan D., additional, Gronthos, Stan, additional, Zannettino, Andrew C.W., additional, and Vandyke, Kate, additional

Published
2020
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30. HIF-2α Promotes Dissemination of Plasma Cells in Multiple Myeloma by Regulating CXCL12/CXCR4 and CCR1

Author

Vandyke, Kate, primary, Zeissig, Mara N., additional, Hewett, Duncan R., additional, Martin, Sally K., additional, Mrozik, Krzysztof M., additional, Cheong, Chee Man, additional, Diamond, Peter, additional, To, L. Bik, additional, Gronthos, Stan, additional, Peet, Daniel J., additional, Croucher, Peter I., additional, and Zannettino, Andrew C.W., additional

Published
2017
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37. Single-nucleotide polymorphism alleles in the insulin receptor gene are associated with typical migraine

Author

McCarthy, Linda C., Hosford, David A., Riley, John H., Bird, Michael I., White, Nicola J., Hewett, Duncan R., Peroutka, Stephen J., Griffiths, Lyn R., Boyd, Pete R., Lea, Rod A., Bhatti, Shahid M., Hosking, Louise K., Hood, Chris M., Jones, Keith W., Handley, Abigail R., Rallan, Raj, Lewis, Karen F., Yeo, Astrid J., Williams, Pauline M., Priest, Richard C., Khan, Parveen, Donnelly, Christine, Lumsden, Sheena M., O'Sullivan, Jennifer, See, Chee Gee, Smart, Devi H., Shaw-Hawkins, Sue, Patel, Jaymini, Langrish, Tony C., Feniuk, Wasyl, Knowles, Richard G., Thomas, Malcolm, Libri, Vincenzo, Montgomery, Doug S., Manasco, Penny K., Xu, Chun-Fang, Dykes, Colin, Humphrey, Patrick P.A., Roses, Allen D., Purvis, Ian J., McCarthy, Linda C., Hosford, David A., Riley, John H., Bird, Michael I., White, Nicola J., Hewett, Duncan R., Peroutka, Stephen J., Griffiths, Lyn R., Boyd, Pete R., Lea, Rod A., Bhatti, Shahid M., Hosking, Louise K., Hood, Chris M., Jones, Keith W., Handley, Abigail R., Rallan, Raj, Lewis, Karen F., Yeo, Astrid J., Williams, Pauline M., Priest, Richard C., Khan, Parveen, Donnelly, Christine, Lumsden, Sheena M., O'Sullivan, Jennifer, See, Chee Gee, Smart, Devi H., Shaw-Hawkins, Sue, Patel, Jaymini, Langrish, Tony C., Feniuk, Wasyl, Knowles, Richard G., Thomas, Malcolm, Libri, Vincenzo, Montgomery, Doug S., Manasco, Penny K., Xu, Chun-Fang, Dykes, Colin, Humphrey, Patrick P.A., Roses, Allen D., and Purvis, Ian J.

Abstract

We have identified a migraine locus on chromosome 19p13.3/2 using linkage and association analysis. We isolated 48 single-nucleotide polymorphisms within the locus, of which we genotyped 24 in a Caucasian population comprising 827 unrelated cases and 765 controls. Five single-nucleotide polymorphisms within the insulin receptor gene showed significant association with migraine. This association was independently replicated in a case-control population collected separately. We used experiments with insulin receptor RNA and protein to investigate functionality for the migraine-associated single-nucleotide polymorphisms. We suggest possible functions for the insulin receptor in migraine pathogenesis.

Published
2002

38. A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q– syndrome

Author

Barlow, Jillian L, primary, Drynan, Lesley F, additional, Hewett, Duncan R, additional, Holmes, Luke R, additional, Lorenzo-Abalde, Silvia, additional, Lane, Alison L, additional, Jolin, Helen E, additional, Pannell, Richard, additional, Middleton, Angela J, additional, Wong, See Heng, additional, Warren, Alan J, additional, Wainscoat, James S, additional, Boultwood, Jacqueline, additional, and McKenzie, Andrew N J, additional

Published
2009
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39. Single-nucleotide polymorphism alleles in the insulin receptor gene are associated with typical migraine

Author

McCarthy, Linda C., Hosford, David A., Riley, John H., Bird, Michael I., White, Nicola J., Hewett, Duncan R., Peroutka, Stephen J., Griffiths, Lyn R., Boyd, Pete R., Lea, Rod A., Bhatti, Shahid M., Hosking, Louise K., Hood, Chris M., Jones, Keith W., Handley, Abigail R., Rallan, Raj, Lewis, Karen F., Yeo, Astrid J.M., Williams, Pauline M., Priest, Richard C., Khan, Parveen, Donnelly, Christine, Lumsden, Sheena M., O'Sullivan, Jennifer, See, Chee Gee, Smart, Devi H., Shaw-Hawkins, Sue, Patel, Jaymini, Langrish, Tony C., Feniuk, Wasyl, Knowles, Richard G., Thomas, Malcolm, Libri, Vincenzo, Montgomery, Doug S., Manasco, Penny K., Xu, Chun Fang, Dykes, Colin, Humphrey, Patrick P.A., Roses, Allen D., Purvis, Ian J., McCarthy, Linda C., Hosford, David A., Riley, John H., Bird, Michael I., White, Nicola J., Hewett, Duncan R., Peroutka, Stephen J., Griffiths, Lyn R., Boyd, Pete R., Lea, Rod A., Bhatti, Shahid M., Hosking, Louise K., Hood, Chris M., Jones, Keith W., Handley, Abigail R., Rallan, Raj, Lewis, Karen F., Yeo, Astrid J.M., Williams, Pauline M., Priest, Richard C., Khan, Parveen, Donnelly, Christine, Lumsden, Sheena M., O'Sullivan, Jennifer, See, Chee Gee, Smart, Devi H., Shaw-Hawkins, Sue, Patel, Jaymini, Langrish, Tony C., Feniuk, Wasyl, Knowles, Richard G., Thomas, Malcolm, Libri, Vincenzo, Montgomery, Doug S., Manasco, Penny K., Xu, Chun Fang, Dykes, Colin, Humphrey, Patrick P.A., Roses, Allen D., and Purvis, Ian J.

Abstract

We have identified a migraine locus on chromosome 19p13.3/2 using linkage and association analysis. We isolated 48 single-nucleotide polymorphisms within the locus, of which we genotyped 24 in a Caucasian population comprising 827 unrelated cases and 765 controls. Five single-nucleotide polymorphisms within the insulin receptor gene showed significant association with migraine. This association was independently replicated in a case-control population collected separately. We used experiments with insulin receptor RNA and protein to investigate functionality for the migraine-associated single-nucleotide polymorphisms. We suggest possible functions for the insulin receptor in migraine pathogenesis.

Published
2001

42. Single-Nucleotide Polymorphism Alleles in the Insulin Receptor Gene Are Associated with Typical Migraine

Author

McCarthy, Linda C., primary, Hosford, David A., additional, Riley, John H., additional, Bird, Michael I., additional, White, Nicola J., additional, Hewett, Duncan R., additional, Peroutka, Stephen J., additional, Griffiths, Lyn R., additional, Boyd, Pete R., additional, Lea, Rod A., additional, Bhatti, Shahid M., additional, Hosking, Louise K., additional, Hood, Chris M., additional, Jones, Keith W., additional, Handley, Abigail R., additional, Rallan, Raj, additional, Lewis, Karen F., additional, Yeo, Astrid J.M., additional, Williams, Pauline M., additional, Priest, Richard C., additional, Khan, Parveen, additional, Donnelly, Christine, additional, Lumsden, Sheena M., additional, O'Sullivan, Jennifer, additional, See, Chee Gee, additional, Smart, Devi H., additional, Shaw-Hawkins, Sue, additional, Patel, Jaymini, additional, Langrish, Tony C., additional, Feniuk, Wasyl, additional, Knowles, Richard G., additional, Thomas, Malcolm, additional, Libri, Vincenzo, additional, Montgomery, Doug S., additional, Manasco, Penny K., additional, Xu, Chun-Fang, additional, Dykes, Colin, additional, Humphrey, Patrick P.A., additional, Roses, Allen D., additional, and Purvis, Ian J., additional

Published
2002
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43. Single-Nucleotide Polymorphism Alleles in the Insulin Receptor Gene Are Associated with Typical Migraine

Author

McCarthy, Linda C., primary, Hosford, David A., additional, Riley, John H., additional, Bird, Michael I., additional, White, Nicola J., additional, Hewett, Duncan R., additional, Peroutka, Stephen J., additional, Griffiths, Lyn R., additional, Boyd, Pete R., additional, Lea, Rod A., additional, Bhatti, Shahid M., additional, Hosking, Louise K., additional, Hood, Chris M., additional, Jones, Keith W., additional, Handley, Abigail R., additional, Rallan, Raj, additional, Lewis, Karen F., additional, Yeo, Astrid J.M., additional, Williams, Pauline M., additional, Priest, Richard C., additional, Khan, Parveen, additional, Donnelly, Christine, additional, Lumsden, Sheena M., additional, O'Sullivan, Jennifer, additional, See, Chee Gee, additional, Smart, Devi H., additional, Shaw-Hawkins, Sue, additional, Patel, Jaymini, additional, Langrish, Tony C., additional, Feniuk, Wasyl, additional, Knowles, Richard G., additional, Thomas, Malcolm, additional, Libri, Vincenzo, additional, Montgomery, Doug S., additional, Manasco, Penny K., additional, Xu, Chun-Fang, additional, Dykes, Colin, additional, Humphrey, Patrick P.A., additional, Roses, Allen D., additional, and Purvis, Ian J., additional

Published
2001
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46. HIF-2α Upregulates CCR1 to Promote Dissemination of Plasma Cells in Multiple Myeloma

Author

Zeissig, Mara N, Hewett, Duncan R., Martin, Sally, Mrozik, Krzysztof M, Cheong, Chee Man, Diamond, Peter, To, Luen Bik, Gronthos, Stan, Peet, Daniel J, Croucher, Peter I, Vandyke, Kate, and Zannettino, Andrew C.W.

Abstract

Introduction:Multiple myeloma (MM) disease progression and relapse is dependent on the ability of the MM plasma cells (PC) to leave the bone marrow, re-enter the circulation and disseminate to other sites throughout the skeleton. Recent data suggests that increased bone marrow hypoxia is associated with increased recirculation of MM PC (Azab et. al. Blood 2012), suggesting that hypoxia may act as a stimulus for dissemination of MM PC. However, the mechanisms responsible for this phenomenon remain unclear. In this study, we identified a potential driver of hypoxia-mediated dissemination of MM PC.

Published
2017
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47. Expression of the chemokine receptor CCR1 promotes the dissemination of multiple myeloma plasma cells in vivo

Author

Zeissig, Mara N, Hewett, Duncan R, Panagopoulos, Vasilios, Mrozik, Krzysztof M, To, L Bik, Croucher, Peter ., Zannettino, Andrew CW, and Vandyke, Kate

Subjects
CXCL12-mediated retention, BM stromal cells, plasma cells
Abstract

Multiple myeloma (MM) disease progression is dependent on the ability of MM plasma cells (PCs) to egress from the bone marrow (BM), enter the circulation and disseminate to distal BM sites. Expression of the chemokine CXCL12 by BM stromal cells is crucial for MM PC retention within the BM. However, the mechanisms which overcome CXCL12-mediated retention to enable dissemination are poorly understood. We have previously identified that treatment with the CCR1 ligand CCL3 inhibits the response to CXCL12 in MM cell lines, suggesting that CCL3/CCR1 signalling may enable egress of MM PC from the BM. Here, we demonstrated that CCR1 expression was an independent prognostic indicator in newly diagnosed MM patients. Furthermore, we showed that CCR1 is a crucial driver of dissemination in vivo, with CCR1 expression in the murine MM cell line 5TGM1 being associated with an increased incidence of bone and splenic disseminated tumours in C57BL/KaLwRij mice. Furthermore, we demonstrated that CCR1 knockout in the human myeloma cell line OPM2 resulted in a >95% reduction in circulating MM PC numbers and BM and splenic tumour dissemination following intratibial injection in NSG mice. Therapeutic targeting of CCR1 with the inhibitor CCX9588 significantly reduced OPM2 or RPMI-8226 dissemination in intratibial xenograft models. Collectively, our findings suggest a novel role for CCR1 as a critical driver of BM egress of MM PCs during tumour dissemination. Furthermore, these data suggest that CCR1 may represent a potential therapeutic target for the prevention of MM tumour dissemination. Refereed/Peer-reviewed

Published
2021

48. Sphingosine kinase 2 inhibition synergises with bortezomib to target myeloma by enhancing endoplasmic reticulum stress

Author

Craig T. Wallington-Beddoe, Melissa R. Pitman, Melissa K. Bennett, Andrew C.W. Zannettino, Paul A.B. Moretti, Julia R. Zebol, Duncan R. Hewett, Kate Vandyke, Stuart M. Pitson, Lorena T. Davies, Wallington-Beddoe, Craig T, Bennett, Melissa K, Vandyke, Kate, Davies, Lorena, Zebol, Julia R, Moretti, Paul AB, Pitman, Melissa R, Hewett, Duncan R, Zannettino, Andrew CW, and Pitson, Stuart M

Subjects
0301 basic medicine, Sphingosine kinase, Antineoplastic Agents, Apoptosis, Models, Biological, Bortezomib, 03 medical and health sciences, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, Cell Line, Tumor, medicine, Animals, Humans, Molecular Targeted Therapy, Cell Death, Dose-Response Relationship, Drug, proteasome inhibitor, Kinase, business.industry, Endoplasmic reticulum, Sphingosine Kinase 2, Drug Synergism, Endoplasmic Reticulum Stress, Xenograft Model Antitumor Assays, Sphingolipid, 3. Good health, Disease Models, Animal, Phosphotransferases (Alcohol Group Acceptor), endoplasmic reticulum, myeloma, 030104 developmental biology, Oncology, sphingosine kinase, 030220 oncology & carcinogenesis, Immunology, Proteasome inhibitor, Unfolded protein response, Cancer research, Multiple Myeloma, business, Proteasome Inhibitors, Priority Research Paper, medicine.drug
Abstract

// Craig T. Wallington-Beddoe 1,2,3 , Melissa K. Bennett 1,2,3 , Kate Vandyke 2,3,4 , Lorena Davies 1,2 , Julia R. Zebol 1,2 , Paul A.B. Moretti 1,2 , Melissa R. Pitman 1,2 , Duncan R. Hewett 3,4 , Andrew C.W. Zannettino 1,2,3,4,* and Stuart M. Pitson 1,2,3,* 1 Center for Cancer Biology, University of South Australia, Adelaide, Australia 2 SA Pathology, Adelaide, Australia 3 School of Medicine, University of Adelaide, Australia 4 South Australian Health and Medical Research Institute, Adelaide, Australia * Co-senior authorship of this article Correspondence to: Andrew C.W. Zannettino, email: // Stuart M. Pitson, email: // Keywords : myeloma, endoplasmic reticulum, proteasome inhibitor, sphingosine kinase Received : March 29, 2017 Accepted : April 04, 2017 Published : April 14, 2017 Abstract The proteasome inhibitor bortezomib has proven to be invaluable in the treatment of myeloma. By exploiting the inherent high immunoglobulin protein production of malignant plasma cells, bortezomib induces endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), resulting in myeloma cell death. In most cases, however, the disease remains incurable highlighting the need for new therapeutic targets. Sphingosine kinase 2 (SK2) has been proposed as one such therapeutic target for myeloma. Our observations that bortezomib and SK2 inhibitors independently elicited induction of ER stress and the UPR prompted us to examine potential synergy between these agents in myeloma. Targeting SK2 synergistically contributed to ER stress and UPR activation induced by bortezomib, as evidenced by activation of the IRE1 pathway and stress kinases JNK and p38MAPK, thereby resulting in potent synergistic myeloma apoptosis in vitro . The combination of bortezomib and SK2 inhibition also exhibited strong in vivo synergy and favourable effects on bone disease. Therefore, our studies suggest that perturbations of sphingolipid signalling can synergistically enhance the effects seen with proteasome inhibition, highlighting the potential for the combination of these two modes of increasing ER stress to be formally evaluated in clinical trials for the treatment of myeloma patients.

Published
2017

49. Clodronate-liposome mediated macrophage depletion abrogates multiple myeloma tumor establishment in vivo

Author

Khatora S. Opperman, Kate Vandyke, Elizabeth A. Coulter, Andreas Evdokiou, Krzysztof M. Mrozik, Kimberley C. Clark, N. Schwarz, Peter I. Croucher, Jacqueline E. Noll, Peter J. Psaltis, Duncan R. Hewett, Andrew C.W. Zannettino, Opperman, Khatora S, Vandyke, Kate, Clark, Kimberley C, Coulter, Elizabeth A, Hewett, Duncan R, Mrozik, Krzysztof M, Schwarz, Nisha, Evdokiou, Andreas, Croucher, Peter I, Psaltis, Peter J, Noll, Jacqueline E, and Zannettino, Andrew CW

Subjects
0301 basic medicine, Original article, Cancer Research, medicine.medical_treatment, Cell Count, Plasma cell, Immunophenotyping, Mice, 03 medical and health sciences, 0302 clinical medicine, Cell Movement, Cell Line, Tumor, hemic and lymphatic diseases, Tumor Microenvironment, Animals, Medicine, Multiple myeloma, Tumor microenvironment, Osteoblasts, Bone Density Conservation Agents, business.industry, Macrophages, Growth factor, Mesenchymal stem cell, medicine.disease, 3. Good health, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Liposomes, Cancer research, Clodronic acid, Disease Susceptibility, Bone marrow, Clodronic Acid, Multiple Myeloma, business, Biomarkers, medicine.drug
Abstract

Multiple myeloma is a fatal plasma cell malignancy that is reliant on the bone marrow microenvironment. The bone marrow is comprised of numerous cells of mesenchymal and hemopoietic origin. Of these, macrophages have been implicated to play a role in myeloma disease progression, angiogenesis, and drug resistance; however, the role of macrophages in myeloma disease establishment remains unknown. In this study, the antimyeloma efficacy of clodronate-liposome treatment, which globally and transiently depletes macrophages, was evaluated in the well-established C57BL/KaLwRijHsd murine model of myeloma. Our studies show, for the first time, that clodronate-liposome pretreatment abrogates myeloma tumor development in vivo. Clodronate-liposome administration resulted in depletion of CD169+ bone marrow–resident macrophages. Flow cytometric analysis revealed that clodronate-liposome pretreatment impaired myeloma plasma cell homing and retention within the bone marrow 24 hours postmyeloma plasma cell inoculation. This was attributed in part to decreased levels of macrophage-derived insulin-like growth factor 1. Moreover, a single dose of clodronate-liposome led to a significant reduction in myeloma tumor burden in KaLwRij mice with established disease. Collectively, these findings support a role for CD169-expressing bone marrow–resident macrophages in myeloma disease establishment and progression and demonstrate the potential of targeting macrophages as a therapy for myeloma patients. Refereed/Peer-reviewed

Published
2019

50. HIF-2α Promotes Dissemination of Plasma Cells in Multiple Myeloma by Regulating CXCL12/CXCR4 and CCR1

Author

Daniel J. Peet, Chee Man Cheong, Stan Gronthos, Duncan R. Hewett, Kate Vandyke, Sally Martin, Krzysztof M. Mrozik, Peter Diamond, Mara N Zeissig, L. Bik To, Andrew C.W. Zannettino, Peter I. Croucher, Vandyke, Kate, Zeissig, Mara N, Hewett, Duncan R, Martin, Sally K, Mrozik, Krzysztof M, Cheong, Chee Man, Diamond, Peter, To, L Bik, Gronthos, Stan, Peet, Daniel J, Croucher, Peter I, and Zannettino, Andrew CW

Subjects
CCR1, Adult, Male, Cancer Research, Receptors, CXCR4, Plasma Cells, Receptors, CCR1, bone marrow hypoxia, CCL3, CXCR4, 03 medical and health sciences, Chemokine receptor, 0302 clinical medicine, Downregulation and upregulation, immune system diseases, hemic and lymphatic diseases, medicine, Basic Helix-Loop-Helix Transcription Factors, Tumor Cells, Cultured, Humans, Multiple myeloma, Aged, Aged, 80 and over, business.industry, Gene Expression Profiling, Mesenchymal stem cell, Middle Aged, medicine.disease, Chemokine CXCL12, myeloma, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Immunology, Cancer research, Disease Progression, Female, Bone marrow, business, Multiple Myeloma, 030215 immunology
Abstract

Disease progression and relapse in multiple myeloma is dependent on the ability of the multiple myeloma plasma cells (PC) to reenter the circulation and disseminate throughout the bone marrow. Increased bone marrow hypoxia is associated with increased recirculation of multiple myeloma PCs. Accordingly, we hypothesized that during chronic hypoxia, activation of HIF-2α may overcome the bone marrow retention signal provided by stromal-derived CXCL12, thereby enabling dissemination of multiple myeloma PCs. Here we demonstrate that HIF-2α upregulates multiple myeloma PC CXCL12 expression, decreasing migration toward CXCL12 and reducing adhesion to mesenchymal stromal cells in vitro. We also found that HIF-2α strongly induced expression of the chemokine receptor CCR1 in multiple myeloma PCs. CCR1 activation potently induces multiple myeloma PC migration toward CCL3 while abrogating the multiple myeloma PC migratory response to CXCL12. In addition, increased CCR1 expression by multiple myeloma PCs conferred poor prognosis in newly diagnosed multiple myeloma patients and was associated with an increase in circulating multiple myeloma PCs in these patients. Taken together, our results suggest a role for hypoxia-mediated CCR1 upregulation in driving the egress of multiple myeloma PCs from the bone marrow. Targeting CCR1 may represent a novel strategy to prevent dissemination and overt relapse in multiple myeloma. Cancer Res; 77(20); 5452–63. ©2017 AACR.

Published
2017

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