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3. Figure S1 from Extracellular S100A9 Protein in Bone Marrow Supports Multiple Myeloma Survival by Stimulating Angiogenesis and Cytokine Secretion

Author

De Veirman, Kim, primary, De Beule, Nathan, primary, Maes, Ken, primary, Menu, Eline, primary, De Bruyne, Elke, primary, De Raeve, Hendrik, primary, Fostier, Karel, primary, Moreaux, Jérôme, primary, Kassambara, Alboukadel, primary, Hose, Dirk, primary, Heusschen, Roy, primary, Eriksson, Helena, primary, Vanderkerken, Karin, primary, and Van Valckenborgh, Els, primary

Published
2023
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4. Supplementary Data from Extracellular S100A9 Protein in Bone Marrow Supports Multiple Myeloma Survival by Stimulating Angiogenesis and Cytokine Secretion

Author

De Veirman, Kim, primary, De Beule, Nathan, primary, Maes, Ken, primary, Menu, Eline, primary, De Bruyne, Elke, primary, De Raeve, Hendrik, primary, Fostier, Karel, primary, Moreaux, Jérôme, primary, Kassambara, Alboukadel, primary, Hose, Dirk, primary, Heusschen, Roy, primary, Eriksson, Helena, primary, Vanderkerken, Karin, primary, and Van Valckenborgh, Els, primary

Published
2023
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5. Supplementary Table 1 from Extracellular S100A9 Protein in Bone Marrow Supports Multiple Myeloma Survival by Stimulating Angiogenesis and Cytokine Secretion

Author

De Veirman, Kim, primary, De Beule, Nathan, primary, Maes, Ken, primary, Menu, Eline, primary, De Bruyne, Elke, primary, De Raeve, Hendrik, primary, Fostier, Karel, primary, Moreaux, Jérôme, primary, Kassambara, Alboukadel, primary, Hose, Dirk, primary, Heusschen, Roy, primary, Eriksson, Helena, primary, Vanderkerken, Karin, primary, and Van Valckenborgh, Els, primary

Published
2023
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6. Data from Extracellular S100A9 Protein in Bone Marrow Supports Multiple Myeloma Survival by Stimulating Angiogenesis and Cytokine Secretion

Author

De Veirman, Kim, primary, De Beule, Nathan, primary, Maes, Ken, primary, Menu, Eline, primary, De Bruyne, Elke, primary, De Raeve, Hendrik, primary, Fostier, Karel, primary, Moreaux, Jérôme, primary, Kassambara, Alboukadel, primary, Hose, Dirk, primary, Heusschen, Roy, primary, Eriksson, Helena, primary, Vanderkerken, Karin, primary, and Van Valckenborgh, Els, primary

Published
2023
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9. Chemokines modulate glycan binding and immunoregulatory activity of galectins

Author

Sanjurjo, Lucia, primary, Schulkens, Iris, additional, Touarin, Pauline, additional, Heusschen, Roy, additional, Aanhane, Ed, additional, Castricum, Kitty, additional, de Gruijl, Tanja, additional, Nilsson, Ulf, additional, Lefler, Hakon, additional, Griffioen, Arjan, additional, Elantak, Latifa, additional, Koenen, Rory, additional, and Thijssen, Victor, additional

Published
2021
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10. Maternal embryonic leucine zipper kinase inhibitor OTSSP167 has preclinical activity in multiple myeloma bone disease

Author

Muller, Joséphine, Bolomsky, Arnold, Dubois, Sophie, Duray, Elodie, Stangelberger, Kathrin, Plougonven, Erwan, Lejeune, Margaux, Léonard, Angélique, Marty, Caroline, Hempel, Ute, Baron, Frédéric, Beguin, Yves, Cohen-Solal, Martine, Ludwig, Heinz, Heusschen, Roy, and Caers, Jo

Subjects
Osteoblasts, Mothers, Osteoclasts, Osteolysis, Protein Serine-Threonine Kinases, Article, Plasma Cell Disorders, Cell Line, Mice, Animals, Heterografts, Humans, Female, Bone Diseases, Naphthyridines, Multiple Myeloma, Protein Kinase Inhibitors, Cell Proliferation
Abstract

Multiple myeloma bone disease is characterized by an uncoupling of bone remodeling in the multiple myeloma microenvironment, resulting in the development of lytic bone lesions. Most myeloma patients suffer from these bone lesions, which not only cause morbidity but also negatively impact survival. The development of novel therapies, ideally with a combined anti-resorptive and bone-anabolic effect, is of great interest because lesions persist with the current standard of care, even in patients in complete remission. We have previously shown that MELK plays a central role in proliferation-associated high-risk multiple myeloma and its inhibition with OTSSP167 resulted in decreased tumor load. MELK inhibition in bone cells has not yet been explored, although some reports suggest that factors downstream of MELK stimulate osteoclast activity and inhibit osteoblast activity, which makes MELK inhibition a promising therapeutic approach. Therefore, we assessed the effect of OTSSP167 on bone cell activity and the development of myeloma-induced bone disease. OTSSP167 inhibited osteoclast activity in vitro by decreasing progenitor viability as well as via a direct anti-resorptive effect on mature osteoclasts. In addition, OTSSP167 stimulated matrix deposition and mineralization by osteoblasts in vitro. This combined anti-resorptive and osteoblast-stimulating effect of OTSSP167 resulted in the complete prevention of lytic lesions and bone loss in myeloma-bearing mice. Immunohistomorphometric analyses corroborated our in vitro findings. In conclusion, we show that OTSSP167 has a direct effect on myeloma-induced bone disease in addition to its anti-multiple myeloma effect, which warrants further clinical development of MELK inhibition in multiple myeloma.

Published
2018

11. Altered chondrocyte differentiation, matrix mineralization and MEK-Erk1/2 signaling in an INPPL1 catalytic knock-out mouse model of opsismodysplasia

Author

Vande Catsyne, Charles-Andrew, primary, Sayyed, Sufyan Ali, additional, Molina-Ortiz, Patricia, additional, Moes, Bastien, additional, Communi, David, additional, Muller, Joséphine, additional, Heusschen, Roy, additional, Caers, Jo, additional, Azzi, Abdelhalim, additional, Erneux, Christophe, additional, and Schurmans, Stéphane, additional

Published
2020
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12. Altered chondrocyte differentiation, matrix mineralization and MEK-Erk1/2 signaling in an INPPL1 catalytic knock-out mouse model of opsismodysplasia

Author

Vande Catsyne, Charles Andrew, Sayyed, Sufyan Ali, Molina-Ortiz, Patricia, Moes, Bastien, Communi, David, Muller, Joséphine, Heusschen, Roy, Caers, Jo, Azzi, Abdelhalim, Erneux, Christophe, Schurmans, Stéphane, Vande Catsyne, Charles Andrew, Sayyed, Sufyan Ali, Molina-Ortiz, Patricia, Moes, Bastien, Communi, David, Muller, Joséphine, Heusschen, Roy, Caers, Jo, Azzi, Abdelhalim, Erneux, Christophe, and Schurmans, Stéphane

Abstract

Opsismodysplasia (OPS) is a rare but severe autosomal recessive skeletal chondrodysplasia caused by inactivating mutations in the Inppl1/Ship2 gene. The molecular mechanism leading from Ship2 gene inactivation to OPS is currently unknown. Here, we used our Ship2Δ/Δ mouse expressing reduced amount of a catalytically-inactive SHIP2 protein and a previously reported SHIP2 inhibitor to investigate growth plate development and mineralization in vivo, ex vivo and in vitro. First, as observed in OPS patients, catalytic inactivation of SHIP2 in mouse leads to reduced body length, shortening of long bones, craniofacial dysmorphism, reduced height of the hyperthrophic chondrocyte zone and to defects in growth plate mineralization. Second, intrinsic Ship2Δ/Δ bone defects were sufficient to induce the characteristic OPS alterations in bone growth, histology and mineralization ex vivo. Third, expression of osteocalcin was significantly increased in SHIP2-inactivated chondrocyte cultures whereas production of mineralized nodules was markedly decreased. Targeting osteocalcin mRNA with a specific shRNA increased the production of mineralized nodules. Fourth, levels of p-MEK and p-Erk1/2 were significantly increased in SHIP2-inactivated chondrocytes in response to serum and IGF-1, but not to FGF2, as compared to control chondrocytes. Treatment of chondrocytes and bones in culture with a MEK inhibitor partially rescued the production of mineralized nodules, the size of the hypertrophic chondrocyte zone and bone growth, raising the possibility of a treatment that could partially reduce the phenotype of this severe condition. Altogether, our results indicate that Ship2Δ/Δ mice represent a relevant model for human OPS. They also highlight the important role of SHIP2 in chondrocytes during endochondral ossification and its different differentiation steps. Finally, we identified a role of osteocalcin in mineralized nodules production and for the MEK-Erk1/2 signaling pathway in the OPS phe, SCOPUS: ar.k, info:eu-repo/semantics/published

Published
2019

13. Inhibition of multiple myeloma exosomes prevents bone loss and reduces tumor growth

Author

Faict, Sylvia T., De Veirman, Kim, Maes, Ken, De Bruyne, Elke, Heusschen, Roy, Caers, Jo, Vanderkerken, Karin, Schots, Rik, Menu, Eline, Basic (bio-) Medical Sciences, Internal Medicine, Faculty of Medicine and Pharmacy, Hematology, Clinical sciences, and Laboratory of Molecullar and Cellular Therapy

Abstract

not available

Published
2018

14. Loss of Stromal Galectin-1 Enhances Multiple Myeloma Development: Emphasis on a Role in Osteoclasts

Author

Muller, Joséphine, primary, Duray, Elodie, additional, Lejeune, Margaux, additional, Dubois, Sophie, additional, Plougonven, Erwan, additional, Léonard, Angélique, additional, Storti, Paola, additional, Giuliani, Nicola, additional, Cohen-Solal, Martine, additional, Hempel, Ute, additional, Thijssen, Victor, additional, Beguin, Yves, additional, Heusschen, Roy, additional, and Caers, Jo, additional

Published
2019
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16. The changing landscape of smoldering multiple myeloma: a European perspective

Author

Caers, Jo de Larrea, Carlos Fernández Leleu, Xavier Heusschen, Roy Zojer, Niklas Decaux, Olivier Kastritis, Efstathios Minnema, Monique Jurczyszyn, Artur Beguin, Yves others

Subjects
Health Sciences, Επιστήμες Υγείας
Abstract

Smoldering multiple myeloma (SMM) is an asymptomatic clonal plasma cell disorder and bridges monoclonal gammo- pathyof undetermined significance to multiple myeloma (MM), based on higher levels of circulating monoclonal immunoglobulin and bone marrow plasmocytosis without end-organ damage. Until a Spanish study reported fewer MM-related events and better overall survival among patients with high- risk SMM treated with lenalidomide and dexamethasone, prior studies had failed to show improved survival with earlier intervention,although a reduction in skeletal-related events (without any impact on disease progression) has been described with bisphosphonate use. Risk factors have now been defined, and a subset of ultra-high-risk patients have been reclassified by the International Myeloma Working Group as MM, and thus will require optimal MM treatment, based on biomarkers that identify patients with a >80% risk of progression. The number of these redefined patients is small (~10%), but important to unravel, because theirriskof progression to overt MM is substantial ($80% within 2 years). Patients with a high-risk cytogenetic profile are not yet considered for early treatment, because groups are heterogeneous and risk factors other than cytogenetics are deemed to weight higher. Because patients with ultra-high- risk SMM are now considered as MM and may be treated as such, concerns exist that earlier therapy may increase the risk of selecting resistant clones and induce side effects and costs. Therefore, an even more accurate identification of patients who would benefit from interventions needs to be performed, and clinical judgment and careful discussion of pros and cons of treatment initiation need to be undertaken. For the majority of SMM patients, the standard of care remains observation until development of symptomatic MM occurs, encouraging participation in ongoing and upcoming SMM/early MM clinical trials, as well as consideration of bisphosphonate use in patients with early bone loss. © AlphaMed Press 2016.

Published
2016

18. Extracellular S100A9 Protein in Bone Marrow Supports Multiple Myeloma Survival by Stimulating Angiogenesis and Cytokine Secretion

Author

De Veirman, Kim, primary, De Beule, Nathan, additional, Maes, Ken, additional, Menu, Eline, additional, De Bruyne, Elke, additional, De Raeve, Hendrik, additional, Fostier, Karel, additional, Moreaux, Jérôme, additional, Kassambara, Alboukadel, additional, Hose, Dirk, additional, Heusschen, Roy, additional, Eriksson, Helena, additional, Vanderkerken, Karin, additional, and Van Valckenborgh, Els, additional

Published
2017
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23. The SRC kinase inhibitor saracatinib limits the development of osteolytic bone disease in multiple myeloma

Author

Heusschen, Roy, primary, Muller, Josephine, additional, Binsfeld, Marilene, additional, Plougonven, Erwan, additional, Mahli, Nadia, additional, Carmeliet, Geert, additional, Leonard, Angelique, additional, Cohen-Solal, Martine, additional, Vanderkerken, Karin, additional, Beguin, Yves, additional, Menu, Eline, additional, and Caers, Jo, additional

Published
2016
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24. SRC kinase inhibition with saracatinib limits the development of osteolytic bone disease in multiple myeloma

Author

Heusschen, Roy, primary, Muller, Joséphine, additional, Binsfeld, Marilène, additional, Marty, Caroline, additional, Plougonven, Erwan, additional, Dubois, Sophie, additional, Mahli, Nadia, additional, Moermans, Karen, additional, Carmeliet, Geert, additional, Léonard, Angélique, additional, Baron, Frédéric, additional, Beguin, Yves, additional, Menu, Eline, additional, Cohen-Solal, Martine, additional, and Caers, Jo, additional

Published
2016
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25. The Changing Landscape of Smoldering Multiple Myeloma: A European Perspective

Author

Caers, Jo, primary, Fernández de Larrea, Carlos, additional, Leleu, Xavier, additional, Heusschen, Roy, additional, Zojer, Niklas, additional, Decaux, Olivier, additional, Kastritis, Efstathios, additional, Minnema, Monique, additional, Jurczyszyn, Artur, additional, Beguin, Yves, additional, Wäsch, Ralph, additional, Palumbo, Antonio, additional, Dimopoulos, Meletios, additional, Mateos, Maria Victoria, additional, Ludwig, Heinz, additional, and Engelhardt, Monika, additional

Published
2016
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26. The Src Inhibitor AZD0530 Prevents the Development of Osteolytic Bone Disease in Multiple Myeloma

Author

Heusschen, Roy, primary, Muller, Joséphine, additional, Binsfeld, Marilène, additional, Plougonven, Erwan, additional, Mahli, Nadia, additional, Carmeliet, Geert, additional, Léonard, Angélique, additional, Cohen-Solal, Martine, additional, Vanderkerken, Karin, additional, Beguin, Yves, additional, Menu, Eline, additional, and Caers, Jo, additional

Published
2015
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27. Molecular mechanisms, current management and next generation therapy in myeloma bone disease.

Author

Heusschen, Roy, Muller, Joséphine, Duray, Elodie, Withofs, Nadia, Bolomsky, Arnold, Baron, Frédéric, Beguin, Yves, Menu, Eline, Ludwig, Heinz, and Caers, Jo

Subjects
*MULTIPLE myeloma, *BONE diseases, *PAIN management, *GENE therapy, *PATIENTS
Abstract

Multiple myeloma (MM) bone disease is a major cause of morbidity and mortality in MM patients and persists even in patients in remission. This bone disease is caused by an uncoupling of bone remodeling, with increased osteoclast and decreased osteoblast activity and formation, culminating in lytic bone destruction. Bisphosphonates are the current standard of care but new therapies are needed. As the molecular mechanisms controlling MM bone disease are increasingly well understood, new therapeutic targets are extensively explored in the preclinical setting and initial clinical trials with novel compounds now show promising results. In this review, we will provide a comprehensive overview of the biology of MM bone disease, summarize its current clinical management and discuss preclinical and clinical data on next generation therapies. [ABSTRACT FROM AUTHOR]

Published
2018
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30. Maternal Embryonic Leucine Zipper Kinase Inhibitor OTSSP167 Inhibits Osteoclast Activity and Restores Osteoblast Activity in a Murine Model of Multiple Myeloma Bone Disease

Author

Muller, Josephine, Bolomsky, Arnold, Schonfelder, Kathrin, Baron, Frederic, Beguin, Yves, Ludwig, Heinz, Caers, Jo, and Heusschen, Roy

Abstract

Multiple myeloma bone disease (MMBD) is characterized by an increased osteoclast activity and a decreased osteoblast differentiation in the multiple myeloma (MM) microenvironment, resulting in the development of lytic bone lesions. A large majority of MM patients suffer from MMBD, which not only causes morbidity but also negatively impacts patient survival. The development of novel therapies, ideally with a combined anti-resorptive and bone-anabolic effect, is of great interest because lytic lesions persist with the current standard of care, even in patients in complete remission. We have previously shown that maternal embryonic leucine zipper kinase (MELK) drives a high-risk gene network in MM and that MELK inhibition with OTSSP167 reduces tumor development in the 5TGM.1 model. In the current study, we assessed the effect of OTSSP167 treatment on bone cell activity and the development of MMBD.

Published
2017
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31. Maternal embryonic leucine zipper kinase is a novel target for proliferation-associated high-risk myeloma.

Author

Bolomsky A, Heusschen R, Schlangen K, Stangelberger K, Muller J, Schreiner W, Zojer N, Caers J, and Ludwig H

Subjects
Animals, Apoptosis drug effects, Cell Cycle drug effects, Cell Line, Tumor, Humans, Mice, Multiple Myeloma pathology, Naphthyridines pharmacology, Prognosis, Protein Serine-Threonine Kinases metabolism, Risk Assessment, Cell Proliferation drug effects, Multiple Myeloma drug therapy, Protein Serine-Threonine Kinases antagonists & inhibitors
Abstract

Treatment of high-risk patients is a major challenge in multiple myeloma. This is especially true for patients assigned to the gene expression profiling-defined proliferation subgroup. Although recent efforts have identified some key players of proliferative myeloma, genetic interactions and players that can be targeted with clinically effective drugs have to be identified in order to overcome the poor prognosis of these patients. We therefore examined maternal embryonic leucine zipper kinase (MELK) for its implications in hyper-proliferative myeloma and analyzed the activity of the MELK inhibitor OTSSP167 both in vitro and in vivo MELK was found to be significantly overexpressed in the proliferative subgroup of myeloma. This finding translated into poor overall survival in patients with high vs low MELK expression. Enrichment analysis of upregulated genes in myeloma cells of MELK high patients confirmed the strong implications in myeloma cell proliferation. Targeting MELK with OTSSP167 impaired the growth and survival of myeloma cells, thereby affecting central survival factors such as MCL-1 and IRF4 This activity was also observed in the 5TGM.1 murine model of myeloma. OTSSP167 reduced bone marrow infiltration and serum paraprotein levels in a dose-dependent manner. In addition, we revealed a strong link between MELK and other proliferation-associated high-risk genes ( PLK-1, EZH2, FOXM1, DEPDC1 ) and MELK inhibition also impaired the expression of those genes. We therefore conclude that MELK is an essential component of a proliferative gene signature and that pharmacological inhibition of MELK represents an attractive novel approach to overcome the poor prognosis of high-risk patients with a proliferative expression pattern., (Copyright© 2018 Ferrata Storti Foundation.)

Published
2018
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