Dokument: Die Effekte von Lenalidomid auf das Knochenmark-Mikromilieu des multiplen Myeloms
| Titel: | Die Effekte von Lenalidomid auf das Knochenmark-Mikromilieu des multiplen Myeloms | |||||||
| Weiterer Titel: | The Effects of Lenalidomide on the Bone Marrow Microenvironment of Multiple Myeloma | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=71703 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20251216-132524-3 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Deutsch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Jochheim, Romy Katharina [Autor] | |||||||
| Dateien: |
| |||||||
| Beitragende: | Dr. Twarock, Sören [Gutachter] Prof. Dr. Haas, Rainer [Gutachter] | |||||||
| Stichwörter: | Knochenmark-Mikromilieu, multiples Myelom, Lenalidomid | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibungen: | Das multiple Myelom (MM) ist eine bösartige Erkrankung des Knochenmarks (KM) charakterisiert durch eine Vermehrung klonaler Plasmazellen und mündend in Endorganschäden wie eine hämatopoietische Insuffizienz und Osteolysen. Zelluläre Bestandteile des KM-Mikromilieus sind Mesenchymale sowie Hämatopoietische Stamm- und Progenitorzellen (MSPZ und HSPZ). MSPZ sind entscheidend für die Bildung und Funktion des KM-Milieus, während HSPZ die Grundlage für die Versorgung mit reifen Blutzellen darstellen. Die Mechanismen, die zu veränderten Funktionen von MSPZ und HSPZ bei MM führen, sind nicht vollständig geklärt.
Lenalidomid, ein immunmodulierendes Medikament, spielt eine wichtige Rolle in der MM-Therapie. Studien deuten auf eine Wirkung von Lenalidomid auf MSPZ und HSPZ hin, die genauen Mechanismen sind allerdings bisher unzureichend aufgeklärt. Ziel dieser Studie war die Analyse der Effekte von Lenalidomid auf das KM-Milieu, indem MSPZ und HSPZ aus dem KM gesunder Probanden und MM-Patienten isoliert, in vitro mit Lenalidomid inkubiert und funktionell sowie molekular untersucht wurden. HSPZ von MM-Patienten unterschieden sich deutlich in Funktion und Genexpression von gesunden Kontrollen mit 199 differentiell exprimierten Genen. Eine Inkubation mit Lenalidomid kehrte die differentielle Genexpression von 30 dieser Gene wieder um und konnte so in Teilen pathologische Veränderungen revertieren. Untersuchungen der MSPZ von gesunden Probanden und MM-Patienten zeigten 1532 differentiell exprimierte Gene. Weitere Analysen wiesen auf die Beteiligung dieser Gene an der Osteogenese und der Matrix des Mikromilieus hin. Nach Lenalidomid-Inkubation traten Genexpressionsänderungen ausschließlich in MSPZ von MM-Patienten auf, u. a. bezogen auf die mitochondriale Funktion und den Energiestoffwechsel. Lenalidomid konnte die durch das MM induzierte veränderte Genexpression in 110 Genen umkehren. Die Daten zeigen unterschiedliche Effekte von Lenalidomid je nach dem physiologischen Zustand der Zellen. Von potentieller klinischer Bedeutung ist die Umkehrung der MM-assoziierten Veränderungen der Genexpression durch Lenalidomid in HSPZ (30 Gene) und MSPZ (110 Gene), was auf eine teilweise Normalisierung der Genexpressionsprofile hindeuten könnte. Darüber hinaus konnten zahlreiche Gene und Signalwege identifiziert werden, die die eingeschränkte Osteogenese und Hämatopoiese im MM erklären können. Die identifizierten Gene bieten neue Ansätze für gezielte Therapien. Besonders ADGRG7 könnte ein potentielles therapeutisches Ziel im Rahmen von osteolytischen Prozessen darstellen.Multiple Myeloma (MM) is a malignant disease of the bone marrow (BM) characterized by a proliferation of clonal plasma cells resulting in end organ damage such as haematopoietic insufficiency and osteolysis. Important cellular components of the BM microenvironment include mesenchymal and hematopoietic stem and progenitor cells (MSPC and HSPC). The latter form the basis for the lifelong supply of mature blood cells while MSPC play an essential part in the formation and function of the BM microenvironment. The underlying mechanisms that lead to a significantly altered functionality of MSPC and HSPC in MM are not yet fully understood. Lenalidomide, an immunomodulatory drug, represents an important treatment concept for MM. Studies indicate an effect of lenalidomide on MSPC and HSPC, but the exact mechanisms remain unclear. The aim of this study was to analyze the effects of lenalidomide on the BM milieu by isolating MSPC and HSPC from the BM of healthy volunteers and MM patients, treating them in vitro with lenalidomide and testing them at a molecular and functional level. HSPC from MM patients differed significantly in function and gene expression from healthy controls with 199 differentially expressed genes. Incubation with lenalidomide reversed the differential gene expression of 30 of these genes and was thus able to partially reverse pathological changes. Investigations of MSPC from healthy volunteers and MM patients revealed 1532 differentially expressed genes. Further analyses indicated the involvement of these genes in osteogenesis and the matrix of the microenvironment. After lenalidomide incubation, gene expression changes occurred exclusively in MSPC from MM-patients, including genes related to mitochondrial function and energy metabolism. Lenalidomide was able to reverse the altered gene expression induced by MM in 110 genes. These data show that the effect of lenalidomide on the cells varies depending on whether they originate from healthy volunteers or myeloma patients. Of potential clinical relevance is the reversal of MM-associated gene expression changes by lenalidomide in HSPC (30 genes) and MSPC (110 genes), indicating a partial normalization of expression profiles. Moreover, numerous genes and signaling pathways have been identified that may account for the impaired osteogenesis and hematopoiesis in MM. The identified genes may offer new approaches for targeted therapies. In particular ADGRG7 could represent a potential therapeutic target in the context of osteolysis. | |||||||
| Quelle: | 1. Lo Celso, C. and D.T. Scadden, The haematopoietic stem cell niche at a glance. J Cell Sci, 2011. 124(Pt 21): p. 3529-35.
2. Ferraro, F., C.L. Celso, and D. Scadden, Adult stem cells and their niches. Advances in experimental medicine and biology, 2010. 695: p. 155-168.
3. Baccin, C., et al., Combined single-cell and spatial transcriptomics reveal the molecular, cellular and spatial bone marrow niche organization. Nature cell biology, 2020. 22(1): p. 38-48.
4. Kiel, M.J., et al., SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell, 2005. 121(7): p. 1109-21.
5. Acar, M., et al., Deep imaging of bone marrow shows non-dividing stem cells are mainly perisinusoidal. Nature, 2015. 526(7571): p. 126-30.
6. Kunisaki, Y., et al., Arteriolar niches maintain haematopoietic stem cell quiescence. Nature, 2013. 502(7473): p. 637-643.
7. Friedrich, C. and O. Kosmider, The Mesenchymal Niche in Myelodysplastic Syndromes. Diagnostics, 2022. 12(7): p. 1639.
8. Méndez-Ferrer, S., et al., Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature, 2010. 466(7308): p. 829-834.
9. Podar, K., D. Chauhan, and K.C. Anderson, Bone marrow microenvironment and the identification of new targets for myeloma therapy. Leukemia, 2009. 23(1): p. 10-24.
10. Akashi, K., et al., A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature, 2000. 404(6774): p. 193-197.
11. Kondo, M., I.L. Weissman, and K. Akashi, Identification of Clonogenic Common Lymphoid Progenitors in Mouse Bone Marrow. Cell, 1997. 91(5): p. 661-672.
12. Pinho, S. and P.S. Frenette, Haematopoietic stem cell activity and interactions with the niche. Nature Reviews Molecular Cell Biology, 2019. 20(5): p. 303-320.
13. Schofield, R., The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells, 1978. 4(1-2): p. 7-25.
14. Méndez-Ferrer, S., et al., Bone marrow niches in haematological malignancies. Nature Reviews Cancer, 2020. 20(5): p. 285-298.
15. Itkin, T., et al., Distinct bone marrow blood vessels differentially regulate haematopoiesis. Nature, 2016. 532(7599): p. 323-8.
16. Federsppiel, B., et al., Molecular cloning of the cDNA and chromosomal localization of the gene for a putative seven-transmembrane segment (7-TMS) receptor isolated from human spleen. Genomics, 1993. 16(3): p. 707-12.
17. Petit, I., D. Jin, and S. Rafii, The SDF-1-CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis. Trends Immunol, 2007. 28(7): p. 299-307.
18. Bruns, I., et al., Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion. Nature medicine, 2014. 20(11): p. 1315-1320.
19. Ullah, T.R., The role of CXCR4 in multiple myeloma: Cells' journey from bone marrow to beyond. J Bone Oncol, 2019. 17: p. 100253.
20. Oberlin, E., et al., The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature, 1996. 382(6594): p. 833-5.
21. Bakondi, B., et al., SDF-1α secreted by human CD133-derived multipotent stromal cells promotes neural progenitor cell survival through CXCR7. Stem Cells Dev, 2011. 20(6): p. 1021-9.
22. Méndez-Ferrer, S., et al., Haematopoietic stem cell release is regulated by circadian oscillations. Nature, 2008. 452(7186): p. 442-7.
23. Arai, F., et al., Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell, 2004. 118(2): p. 149-61.
24. Davis, S., et al., Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell, 1996. 87(7): p. 1161-9.
25. Puri, M.C. and A. Bernstein, Requirement for the TIE family of receptor tyrosine kinases in adult but not fetal hematopoiesis. Proc Natl Acad Sci U S A, 2003. 100(22): p. 12753-8.
26. Takakura, N., et al., Critical role of the TIE2 endothelial cell receptor in the development of definitive hematopoiesis. Immunity, 1998. 9(5): p. 677-86.
27. Wu, Y., et al., Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis. Stem Cells, 2007. 25(10): p. 2648-59.
28. Kent, D., et al., Regulation of hematopoietic stem cells by the steel factor/KIT signaling pathway. Clin Cancer Res, 2008. 14(7): p. 1926-30.
29. Heissig, B., et al., Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell, 2002. 109(5): p. 625-37.
30. Ikuta, K. and I.L. Weissman, Evidence that hematopoietic stem cells express mouse c-kit but do not depend on steel factor for their generation. Proc Natl Acad Sci U S A, 1992. 89(4): p. 1502-6.
31. Thorén, L.A., et al., Kit regulates maintenance of quiescent hematopoietic stem cells. J Immunol, 2008. 180(4): p. 2045-53.
32. Broudy, V.C., Stem cell factor and hematopoiesis. Blood, 1997. 90(4): p. 1345-64.
33. Nakamura, Y., et al., Isolation and characterization of endosteal niche cell populations that regulate hematopoietic stem cells. Blood, 2010. 116(9): p. 1422-1432.
34. Oldershaw, R.A. and T.E. Hardingham, Notch signaling during chondrogenesis of human bone marrow stem cells. Bone, 2010. 46(2): p. 286-93.
35. Lai, E.C., Notch signaling: control of cell communication and cell fate. Development, 2004. 131(5): p. 965-73.
36. Milner, L.A., et al., A human homologue of the Drosophila developmental gene, Notch, is expressed in CD34+ hematopoietic precursors. Blood, 1994. 83(8): p. 2057-62.
37. Bigas, A. and L. Espinosa, Hematopoietic stem cells: to be or Notch to be. Blood, 2012. 119(14): p. 3226-35.
38. Calvi, L.M., et al., Osteoblastic cells regulate the haematopoietic stem cell niche. Nature, 2003. 425(6960): p. 841-6.
39. Yamazaki, S., et al., TGF-beta as a candidate bone marrow niche signal to induce hematopoietic stem cell hibernation. Blood, 2009. 113(6): p. 1250-6.
40. Yamazaki, S., et al., Nonmyelinating Schwann cells maintain hematopoietic stem cell hibernation in the bone marrow niche. Cell, 2011. 147(5): p. 1146-58.
41. Wang, H., et al., Hierarchical organization and regulation of the hematopoietic stem cell osteoblastic niche. Crit Rev Oncol Hematol, 2013. 85(1): p. 1-8.
42. Reya, T., et al., A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature, 2003. 423(6938): p. 409-414.
43. Bhardwaj, G., et al., Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation. Nature Immunology, 2001. 2(2): p. 172-180.
44. Bhatia, M., et al., Bone Morphogenetic Proteins Regulate the Developmental Program of Human Hematopoietic Stem Cells. Journal of Experimental Medicine, 1999. 189(7): p. 1139-1148.
45. Jäger, P.S., Einfluss von myeloischen Blasten auf gesunde CD34+ hämatopoietische Stamm- und Progenitorzellen. 2019, Heinrich-Heine-Universität Düsseldorf.
46. Geyh, S., Funktionale und molekulare Analysen von Mesenchymalen Stromazellen und deren Interaktionen mit CD34+ Stamm- und Progenitorzellen bei Patienten mit Myelodysplastischen Syndromen. 2013, Heinrich-Heine-Universität Düsseldorf.
47. Dominici, M., et al., Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy, 2006. 8(4): p. 315-7.
48. Pittenger, M.F., et al., Multilineage Potential of Adult Human Mesenchymal Stem Cells. Science, 1999. 284(5411): p. 143-147.
49. Chichester, C.O., M. Fernández, and J.J. Minguell, Extracellular Matrix Gene Expression by Human Bone Marrow Stroma and by Marrow Fibroblasts. Cell Adhesion and Communication, 1993. 1(2): p. 93-99.
50. Majumdar, M.K., et al., Human marrow-derived mesenchymal stem cells (MSCs) express hematopoietic cytokines and support long-term hematopoiesis when differentiated toward stromal and osteogenic lineages. J Hematother Stem Cell Res, 2000. 9(6): p. 841-8.
51. Verfaillie, C., et al., Role of bone marrow matrix in normal and abnormal hematopoiesis. Critical Reviews in Oncology/Hematology, 1994. 16(3): p. 201-224.
52. Jung, Y., et al., Regulation of SDF-1 (CXCL12) production by osteoblasts; a possible mechanism for stem cell homing. Bone, 2006. 38(4): p. 497-508.
53. Taichman, R.S. and S.G. Emerson, Human osteoblasts support hematopoiesis through the production of granulocyte colony-stimulating factor. Journal of Experimental Medicine, 1994. 179(5): p. 1677-1682.
54. Arai, F., et al., Tie2/Angiopoietin-1 Signaling Regulates Hematopoietic Stem Cell Quiescence in the Bone Marrow Niche. Cell, 2004. 118(2): p. 149-161.
55. Asada, N., et al., Matrix-embedded osteocytes regulate mobilization of hematopoietic stem/progenitor cells. Cell Stem Cell, 2013. 12(6): p. 737-47.
56. Aoki, K., et al., Identification of CXCL12-abundant reticular cells in human adult bone marrow. Br J Haematol, 2021. 193(3): p. 659-668.
57. Sugiyama, T., et al., Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity, 2006. 25(6): p. 977-88.
58. Malaval, L., et al., Cellular expression of bone-related proteins during in vitro osteogenesis in rat bone marrow stromal cell cultures. J Cell Physiol, 1994. 158(3): p. 555-72.
59. Massagué, J., TGF-beta signal transduction. Annu Rev Biochem, 1998. 67: p. 753-91.
60. Heldin, C.H., K. Miyazono, and P. ten Dijke, TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature, 1997. 390(6659): p. 465-71.
61. Gallea, S., et al., Activation of mitogen-activated protein kinase cascades is involved in regulation of bone morphogenetic protein-2-induced osteoblast differentiation in pluripotent C2C12 cells. Bone, 2001. 28(5): p. 491-8.
62. Hanafusa, H., et al., Involvement of the p38 mitogen-activated protein kinase pathway in transforming growth factor-beta-induced gene expression. J Biol Chem, 1999. 274(38): p. 27161-7.
63. Lee, K.S., et al., Runx2 is a common target of transforming growth factor beta1 and bone morphogenetic protein 2, and cooperation between Runx2 and Smad5 induces osteoblast-specific gene expression in the pluripotent mesenchymal precursor cell line C2C12. Mol Cell Biol, 2000. 20(23): p. 8783-92.
64. Komori, T., et al., Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell, 1997. 89(5): p. 755-64.
65. Lee, K.S., S.H. Hong, and S.C. Bae, Both the Smad and p38 MAPK pathways play a crucial role in Runx2 expression following induction by transforming growth factor-beta and bone morphogenetic protein. Oncogene, 2002. 21(47): p. 7156-63.
66. Spinella-Jaegle, S., et al., Opposite effects of bone morphogenetic protein-2 and transforming growth factor-beta1 on osteoblast differentiation. Bone, 2001. 29(4): p. 323-30.
67. Liu, X., et al., Cross-talk between EGF and BMP9 signalling pathways regulates the osteogenic differentiation of mesenchymal stem cells. J Cell Mol Med, 2013. 17(9): p. 1160-72.
68. Zanotti, S. and E. Canalis, Notch Signaling and the Skeleton. Endocr Rev, 2016. 37(3): p. 223-53.
69. Cakouros, D., et al., Novel basic helix-loop-helix transcription factor hes4 antagonizes the function of twist-1 to regulate lineage commitment of bone marrow stromal/stem cells. Stem Cells Dev, 2015. 24(11): p. 1297-308.
70. Tu, X., et al., Physiological notch signaling maintains bone homeostasis via RBPjk and Hey upstream of NFATc1. PLoS Genet, 2012. 8(3): p. e1002577.
71. Engin, F., et al., Dimorphic effects of Notch signaling in bone homeostasis. Nat Med, 2008. 14(3): p. 299-305.
72. Bai, S., et al., NOTCH1 regulates osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblast lineage cells. J Biol Chem, 2008. 283(10): p. 6509-18.
73. Fukushima, H., et al., The association of Notch2 and NF-kappaB accelerates RANKL-induced osteoclastogenesis. Mol Cell Biol, 2008. 28(20): p. 6402-12.
74. Frenquelli, M. and G. Tonon, WNT Signaling in Hematological Malignancies. Frontiers in Oncology, 2020. 10.
75. Gaur, T., et al., Canonical WNT Signaling Promotes Osteogenesis by Directly Stimulating Runx2 Gene Expression*. Journal of Biological Chemistry, 2005. 280(39): p. 33132-33140.
76. Ingham, P.W. and A.P. McMahon, Hedgehog signaling in animal development: paradigms and principles. Genes Dev, 2001. 15(23): p. 3059-87.
77. Shimoyama, A., et al., Ihh/Gli2 signaling promotes osteoblast differentiation by regulating Runx2 expression and function. Mol Biol Cell, 2007. 18(7): p. 2411-8.
78. Cai, J.Q., et al., Sonic hedgehog enhances the proliferation and osteogenic differentiation of bone marrow-derived mesenchymal stem cells. Cell Biol Int, 2012. 36(4): p. 349-55.
79. Zha, K., et al., Recent Advances in Enhancement Strategies for Osteogenic Differentiation of Mesenchymal Stem Cells in Bone Tissue Engineering. Front Cell Dev Biol, 2022. 10: p. 824812.
80. Amarasekara, D.S., S. Kim, and J. Rho, Regulation of Osteoblast Differentiation by Cytokine Networks. International Journal of Molecular Sciences, 2021. 22(6): p. 2851.
81. Chen, J., et al., The Hippo pathway: a renewed insight in the craniofacial diseases and hard tissue remodeling. International journal of biological sciences, 2021. 17(14): p. 4060-4072.
82. Pan, J.-X., et al., YAP promotes osteogenesis and suppresses adipogenic differentiation by regulating β-catenin signaling. Bone Research, 2018. 6(1): p. 18.
83. Seo, E., et al., SOX2 Regulates YAP1 to Maintain Stemness and Determine Cell Fate in the Osteo-Adipo Lineage. Cell Reports, 2013. 3(6): p. 2075-2087.
84. Kern, B., et al., Cbfa1 contributes to the osteoblast-specific expression of type I collagen genes. J Biol Chem, 2001. 276(10): p. 7101-7.
85. Ducy, P., et al., Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell, 1997. 89(5): p. 747-54.
86. Phillips, J.E., et al., Glucocorticoid-induced osteogenesis is negatively regulated by Runx2/Cbfa1 serine phosphorylation. J Cell Sci, 2006. 119(Pt 3): p. 581-91.
87. Komori, T., Runx2, an inducer of osteoblast and chondrocyte differentiation. Histochem Cell Biol, 2018. 149(4): p. 313-323.
88. Ortuño, M.J., et al., Osterix induces Col1a1 gene expression through binding to Sp1 sites in the bone enhancer and proximal promoter regions. Bone, 2013. 52(2): p. 548-56.
89. Yang, Y., et al., Transcriptional regulation of bone sialoprotein gene expression by Osx. Biochem Biophys Res Commun, 2016. 476(4): p. 574-579.
90. Wu, L., et al., Osteogenic differentiation of adipose derived stem cells promoted by overexpression of osterix. Mol Cell Biochem, 2007. 301(1-2): p. 83-92.
91. Luo, K., Signaling Cross Talk between TGF-β/Smad and Other Signaling Pathways. Cold Spring Harbor perspectives in biology, 2017. 9(1): p. a022137.
92. Li, L., et al., Hedgehog signaling is involved in the BMP9-induced osteogenic differentiation of mesenchymal stem cells. Int J Mol Med, 2015. 35(6): p. 1641-1650.
93. Kortüm, M., et al., Leitlinie Multiples Myelom DGHO Deutsche Gesellschaft für Hämatologie und Medizinische Onkologie e.V., 2024.
94. Weber, D.M., Solitary Bone and Extramedullary Plasmacytoma. Hematology, 2005. 2005(1): p. 373-376.
95. Holland, J., et al., Plasmacytoma. Treatment results and conversion to myeloma. Cancer, 1992. 69(6): p. 1513-1517.
96. Rajkumar, S.V., et al., International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. The Lancet Oncology, 2014. 15(12): p. e538-e548.
97. Zentrum für Krebsregisterdaten and G.d.e.K.i.D. e.V., Krebs in Deutschland für 2019/2020. 2023, Robert-Koch-Institut: Berlin.
98. Bray, F., et al., Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 2018. 68(6): p. 394-424.
99. Zentrum für Krebsregisterdaten and G.d.e.K.i.D. e.V., Krebs in Deutschland für 2017/2018. 2021, Robert-Koch-Institut: Berlin.
100. European Medicines Agency. EMA/650468/2019 - Revlimid (Lenalidomid) Übersicht über Revlimid und warum es in der EU zugelassen ist. 2019 20.03.2020].
101. Kotchetkov, R., et al., Secondary primary malignancies during the lenalidomide-dexamethasone regimen in relapsed/refractory multiple myeloma patients. Cancer Med, 2017. 6(1): p. 3-11.
102. McCarthy, P.L., et al., Lenalidomide Maintenance After Autologous Stem-Cell Transplantation in Newly Diagnosed Multiple Myeloma: A Meta-Analysis. Journal of Clinical Oncology, 2017. 35(29): p. 3279-3289.
103. Jackson, G.H., et al., Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol, 2019. 20(1): p. 57-73.
104. Dimopoulos, M., et al., Lenalidomide plus Dexamethasone for Relapsed or Refractory Multiple Myeloma. New England Journal of Medicine, 2007. 357(21): p. 2123-2132.
105. Weber, D.M., et al., Lenalidomide plus Dexamethasone for Relapsed Multiple Myeloma in North America. New England Journal of Medicine, 2007. 357(21): p. 2133-2142.
106. Kumar, S.K., et al., Improved survival in multiple myeloma and the impact of novel therapies. Blood, 2008. 111(5): p. 2516-2520.
107. Kumar, S.K., et al., Multiple myeloma. Nature Reviews Disease Primers, 2017. 3: p. 17046-17046.
108. Bianchi, G. and N.C. Munshi, Pathogenesis beyond the cancer clone(s) in multiple myeloma. Blood, 2015. 125(20): p. 3049-3058.
109. Hargreaves, D.C., et al., A coordinated change in chemokine responsiveness guides plasma cell movements. The Journal of experimental medicine, 2001. 194(1): p. 45-56.
110. Lapidot, T. and O. Kollet, The essential roles of the chemokine SDF-1 and its receptor CXCR4 in human stem cell homing and repopulation of transplanted immune-deficient NOD/SCID and NOD/SCID/B2mnull mice. Leukemia, 2002. 16(10): p. 1992-2003.
111. Nagasawa, T., et al., Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature, 1996. 382(6592): p. 635-638.
112. Zannettino, A.C.W., et al., Elevated Serum Levels of Stromal-Derived Factor-1α Are Associated with Increased Osteoclast Activity and Osteolytic Bone Disease in Multiple Myeloma Patients. Cancer Research, 2005. 65(5): p. 1700-1709.
113. Dar, A., et al., Chemokine receptor CXCR4–dependent internalization and resecretion of functional chemokine SDF-1 by bone marrow endothelial and stromal cells. Nature Immunology, 2005. 6(10): p. 1038-1046.
114. Hideshima, T., et al., Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets. Nat Rev Cancer, 2007. 7(8): p. 585-98.
115. Damiano, J.S., et al., Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines. Blood, 1999. 93(5): p. 1658-1667.
116. Hazlehurst, L.A., et al., Adhesion to fibronectin via β1 integrins regulates p27kip1 levels and contributes to cell adhesion mediated drug resistance (CAM-DR). Oncogene, 2000. 19(38): p. 4319-4327.
117. Li, Z.W., et al., NF-kappaB in the pathogenesis and treatment of multiple myeloma. Curr Opin Hematol, 2008. 15(4): p. 391-9.
118. Colombo, M., et al., Multiple myeloma-derived Jagged ligands increases autocrine and paracrine interleukin-6 expression in bone marrow niche. Oncotarget, 2016. 7(35): p. 56013-56029.
119. Rajkumar, S.V., et al., Bone Marrow Angiogenesis in 400 Patients with Monoclonal Gammopathy of Undetermined Significance, Multiple Myeloma, and Primary Amyloidosis. Clinical Cancer Research, 2002. 8(7): p. 2210-2216.
120. Kishimoto, T., The biology of interleukin-6. Blood, 1989. 74(1): p. 1-10.
121. Terpos, E., et al., Pathogenesis of bone disease in multiple myeloma: from bench to bedside. Blood Cancer Journal, 2018. 8(1): p. 7.
122. Noll, J.E., et al., Myeloma plasma cells alter the bone marrow microenvironment by stimulating the proliferation of mesenchymal stromal cells. Haematologica, 2014. 99(1): p. 163-171.
123. Quach, H., et al., Mechanism of action of immunomodulatory drugs (IMiDS) in multiple myeloma. Leukemia, 2010. 24(1): p. 22-32.
124. Burger, J.A., et al., The microenvironment in mature B-cell malignancies: a target for new treatment strategies. Blood, 2009. 114(16): p. 3367-75.
125. Kyle, R.A., et al., Review of 1027 Patients With Newly Diagnosed Multiple Myeloma. Mayo Clinic Proceedings, 2003. 78(1): p. 21-33.
126. Bruns, I., et al., Multiple myeloma-related deregulation of bone marrow-derived CD34(+) hematopoietic stem and progenitor cells. Blood, 2012. 120(13): p. 2620-30.
127. Silvestris, F., et al., Negative regulation of erythroblast maturation by Fas-L(+)/TRAIL(+) highly malignant plasma cells: a major pathogenetic mechanism of anemia in multiple myeloma. Blood, 2002. 99(4): p. 1305-13.
128. Silvestris, F., et al., Fas-L up-regulation by highly malignant myeloma plasma cells: role in the pathogenesis of anemia and disease progression. Blood, 2001. 97(5): p. 1155-64.
129. Moyo, T.K., et al., Effects of Bone Marrow Infiltration By Multiple Myeloma on Erythropoiesis. Blood, 2015. 126(23): p. 2143-2143.
130. Beguin, Y., et al., Erythropoiesis in multiple myeloma: defective red cell production due to inappropriate erythropoietin production. Br J Haematol, 1992. 82(4): p. 648-53.
131. De Maria, R., et al., Apoptotic role of Fas/Fas ligand system in the regulation of erythropoiesis. Blood, 1999. 93(3): p. 796-803.
132. Bouchnita, A., et al., Bone marrow infiltration by multiple myeloma causes anemia by reversible disruption of erythropoiesis. Am J Hematol, 2016. 91(4): p. 371-8.
133. Maes, K., et al., In anemia of multiple myeloma, hepcidin is induced by increased bone morphogenetic protein 2. Blood, 2010. 116(18): p. 3635-44.
134. Roodman, G.D., Mechanisms of bone lesions in multiple myeloma and lymphoma. Cancer, 1997. 80(S8): p. 1557-1563.
135. Palumbo, A. and K. Anderson, Multiple myeloma. The New England journal of medicine, 2011. 364(11): p. 1046-1060.
136. Standal, T., et al., HGF inhibits BMP-induced osteoblastogenesis: possible implications for the bone disease of multiple myeloma. Blood, 2006. 109(7): p. 3024-3030.
137. Takeuchi, K., et al., Tgf-Beta inhibition restores terminal osteoblast differentiation to suppress myeloma growth. PLoS One, 2010. 5(3): p. e9870.
138. Colombo, M., et al., Notch-directed microenvironment reprogramming in myeloma: a single path to multiple outcomes. Leukemia, 2013. 27(5): p. 1009-1018.
139. Tian, E., et al., The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med, 2003. 349(26): p. 2483-94.
140. Qiang, Y.W., et al., Myeloma-derived Dickkopf-1 disrupts Wnt-regulated osteoprotegerin and RANKL production by osteoblasts: a potential mechanism underlying osteolytic bone lesions in multiple myeloma. Blood, 2008. 112(1): p. 196-207.
141. Tibullo, D., et al., Ixazomib Improves Bone Remodeling and Counteracts sonic Hedgehog signaling Inhibition Mediated by Myeloma Cells. Cancers (Basel), 2020. 12(2).
142. Giuliani, N., et al., Myeloma cells block RUNX2/CBFA1 activity in human bone marrow osteoblast progenitors and inhibit osteoblast formation and differentiation. Blood, 2005. 106(7): p. 2472-83.
143. Davies, F.E., et al., Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood, 2001. 98(1): p. 210-6.
144. Zhu, D., et al., Immunomodulatory drugs Revlimid (lenalidomide) and CC-4047 induce apoptosis of both hematological and solid tumor cells through NK cell activation. Cancer Immunol Immunother, 2008. 57(12): p. 1849-59.
145. Lu, L., et al., The anti-cancer drug lenalidomide inhibits angiogenesis and metastasis via multiple inhibitory effects on endothelial cell function in normoxic and hypoxic conditions. Microvasc Res, 2009. 77(2): p. 78-86.
146. Mitsiades, N., et al., Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. Blood, 2002. 99(12): p. 4525-4530.
147. Wobus, M., et al., Impact of lenalidomide on the functional properties of human mesenchymal stromal cells. Exp Hematol, 2012. 40(10): p. 867-76.
148. Corral, L.G., et al., Selection of Novel Analogs of Thalidomide with Enhanced Tumor Necrosis Factor α Inhibitory Activity. Molecular Medicine, 1996. 2(4): p. 506-515.
149. Corral, L.G., et al., Differential Cytokine Modulation and T Cell Activation by Two Distinct Classes of Thalidomide Analogues That Are Potent Inhibitors of TNF-α. The Journal of Immunology, 1999. 163(1): p. 380-386.
150. Gupta, D., et al., Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: therapeutic applications. Leukemia, 2001. 15(12): p. 1950-61.
151. Ge, N.L. and S. Rudikoff, Insulin-like growth factor I is a dual effector of multiple myeloma cell growth. Blood, 2000. 96(8): p. 2856-61.
152. Terpos, E., et al., Increased circulating VCAM-1 correlates with advanced disease and poor survival in patients with multiple myeloma: reduction by post-bortezomib and lenalidomide treatment. Blood Cancer J, 2016. 6(5): p. e428.
153. Hideshima, T., et al., The role of tumor necrosis factor α in the pathophysiology of human multiple myeloma: therapeutic applications. Oncogene, 2001. 20(33): p. 4519-4527.
154. Hideshima, T., et al., Advances in biology of multiple myeloma: clinical applications. Blood, 2004. 104(3): p. 607-618.
155. Zhu, Y.X., et al., Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide. Blood, 2011. 118(18): p. 4771-9.
156. Kronke, J., et al., Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science, 2014. 343(6168): p. 301-5.
157. Lu, G., et al., The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science, 2014. 343(6168): p. 305-9.
158. Merkenschlager, M., Ikaros in immune receptor signaling, lymphocyte differentiation, and function. FEBS Lett, 2010. 584(24): p. 4910-4.
159. Nooka, A.K. and S. Lonial, Mechanism of Action and Novel IMiD-Based Compounds and Combinations in Multiple Myeloma. Cancer J, 2019. 25(1): p. 19-31.
160. Stewart, A.K., Medicine. How thalidomide works against cancer. Science, 2014. 343(6168): p. 256-7.
161. Robak, P., et al., Drug resistance in multiple myeloma. Cancer Treat Rev, 2018. 70: p. 199-208.
162. Bjorklund, C.C., et al., Evidence of a role for CD44 and cell adhesion in mediating resistance to lenalidomide in multiple myeloma: therapeutic implications. Leukemia, 2014. 28(2): p. 373-83.
163. Zhu, Y.X., et al., Identification of lenalidomide resistance pathways in myeloma and targeted resensitization using cereblon replacement, inhibition of STAT3 or targeting of IRF4. Blood Cancer J, 2019. 9(2): p. 19.
164. Wilk, C.M., et al., Lenalidomide consolidation treatment in patients with multiple myeloma suppresses myelopoieses but spares erythropoiesis. Int J Cancer, 2016. 139(10): p. 2343-52.
165. Muller, G.W., et al., Amino-substituted thalidomide analogs: potent inhibitors of TNF-alpha production. Bioorg Med Chem Lett, 1999. 9(11): p. 1625-30.
166. De Maria, R., et al., Negative regulation of erythropoiesis by caspase-mediated cleavage of GATA-1. Nature, 1999. 401(6752): p. 489-93.
167. Rusten, L.S. and S.E. Jacobsen, Tumor necrosis factor (TNF)-alpha directly inhibits human erythropoiesis in vitro: role of p55 and p75 TNF receptors. Blood, 1995. 85(4): p. 989-96.
168. Cheng, Y., et al., Erythroid GATA1 function revealed by genome-wide analysis of transcription factor occupancy, histone modifications, and mRNA expression. Genome Res, 2009. 19(12): p. 2172-84.
169. Koh, K.R., et al., Immunomodulatory derivative of thalidomide (IMiD CC-4047) induces a shift in lineage commitment by suppressing erythropoiesis and promoting myelopoiesis. Blood, 2005. 105(10): p. 3833-40.
170. Richardson, P., et al., Lenalidomide in multiple myeloma: an evidence-based review of its role in therapy. Core evidence, 2010. 4: p. 215-245.
171. Mintzer, D.M. and S.N. Billet, Efficacy of Lenalidomide for Treatment of Anemia in Secondary Myelodysplastic Syndrome (MDS) with Chromosome 5q Deletion. Blood, 2007. 110(11): p. 4614-4614.
172. Anderson, G., et al., Thalidomide derivative CC-4047 inhibits osteoclast formation by down-regulation of PU.1. Blood, 2006. 107(8): p. 3098-105.
173. Terpos, E., et al., The combination of intermediate doses of thalidomide with dexamethasone is an effective treatment for patients with refractory/relapsed multiple myeloma and normalizes abnormal bone remodeling, through the reduction of sRANKL/osteoprotegerin ratio. Leukemia, 2005. 19(11): p. 1969-76.
174. Tosi, P., et al., First-line therapy with thalidomide, dexamethasone and zoledronic acid decreases bone resorption markers in patients with multiple myeloma. Eur J Haematol, 2006. 76(5): p. 399-404.
175. Tsuda, H., et al., Therapy with lenalidomide plus dexamethasone-induced bone formation in a patient with refractory multiple myeloma. Int J Hematol, 2012. 95(6): p. 706-10.
176. Guo, J., et al., Lenalidomide restores the osteogenic differentiation of bone marrow mesenchymal stem cells from multiple myeloma patients via deactivating Notch signaling pathway. Oncotarget, 2017. 8(33): p. 55405-55421.
177. Terpos, E., et al., The combination of lenalidomide and dexamethasone reduces bone resorption in responding patients with relapsed/refractory multiple myeloma but has no effect on bone formation: final results on 205 patients of the Greek myeloma study group. Am J Hematol, 2014. 89(1): p. 34-40.
178. Breitkreutz, I., et al., Lenalidomide inhibits osteoclastogenesis, survival factors and bone-remodeling markers in multiple myeloma. Leukemia, 2008. 22(10): p. 1925-1932.
179. Bjorklund, C.C., et al., Evidence of a role for activation of Wnt/beta-catenin signaling in the resistance of plasma cells to lenalidomide. J Biol Chem, 2011. 286(13): p. 11009-20.
180. Yin, L., et al., MUC1-C is a target in lenalidomide resistant multiple myeloma. Br J Haematol, 2017. 178(6): p. 914-926.
181. Schindelin, J., et al., Fiji: an open-source platform for biological-image analysis. Nature Methods, 2012. 9(7): p. 676-682.
182. Brocher, J., biovoxxel/BioVoxxel-Toolbox: BioVoxxel Toolbox v2.6.0. 2023: Zenodo.
183. Krämer, A., et al., Causal analysis approaches in Ingenuity Pathway Analysis. Bioinformatics, 2014. 30(4):523–30.
184. Peng, Y., et al., Structural basis of substrate recognition in human nicotinamide N-methyltransferase. Biochemistry, 2011. 50(36): p. 7800-8.
185. Guo, L., et al., Bi-allelic CSF1R Mutations Cause Skeletal Dysplasia of Dysosteosclerosis-Pyle Disease Spectrum and Degenerative Encephalopathy with Brain Malformation. Am J Hum Genet, 2019. 104(5): p. 925-935.
186. Szepessy, E. and M. Sahin-Tóth, Inactivity of recombinant ELA2B provides a new example of evolutionary elastase silencing in humans. Pancreatology, 2006. 6(1-2): p. 117-22.
187. Liu, B., et al., The biology of VSIG4: Implications for the treatment of immune-mediated inflammatory diseases and cancer. Cancer Lett, 2023. 553: p. 215996.
188. Schneider, H., et al., Human cyclophilin C: primary structure, tissue distribution, and determination of binding specificity for cyclosporins. Biochemistry, 1994. 33(27): p. 8218-24.
189. Friedman, J. and I. Weissman, Two cytoplasmic candidates for immunophilin action are revealed by affinity for a new cyclophilin: one in the presence and one in the absence of CsA. Cell, 1991. 66(4): p. 799-806.
190. Bono, P., et al., Layilin, a novel integral membrane protein, is a hyaluronan receptor. Mol Biol Cell, 2001. 12(4): p. 891-900.
191. Colonna, M., TREMs in the immune system and beyond. Nat Rev Immunol, 2003. 3(6): p. 445-53.
192. Cella, M., et al., Impaired differentiation of osteoclasts in TREM-2-deficient individuals. J Exp Med, 2003. 198(4): p. 645-51.
193. Herr, A.B., E.R. Ballister, and P.J. Bjorkman, Insights into IgA-mediated immune responses from the crystal structures of human FcalphaRI and its complex with IgA1-Fc. Nature, 2003. 423(6940): p. 614-20.
194. Domínguez-Berzosa, L., et al., ANKK1 Is a Wnt/PCP Scaffold Protein for Neural F-ACTIN Assembly. Int J Mol Sci, 2024. 25(19).
195. Lipper, C.H., et al., Crystal structure of the Tspan15 LEL domain reveals a conserved ADAM10 binding site. Structure, 2022. 30(2): p. 206-214.e4.
196. Werner, A.C., et al., Coronin 1B Controls Endothelial Actin Dynamics at Cell-Cell Junctions and Is Required for Endothelial Network Assembly. Front Cell Dev Biol, 2020. 8: p. 708.
197. Wang, Y., et al., SLAMF8 regulates osteogenesis and adipogenesis of bone marrow mesenchymal stem cells via S100A6/Wnt/β-catenin signaling pathway. Stem Cell Res Ther, 2024. 15(1): p. 349.
198. Skokowa, J., et al., Severe congenital neutropenias. Nat Rev Dis Primers, 2017. 3: p. 17032.
199. Dalakas, M.C. and P.J. Spaeth, The importance of FcRn in neuro-immunotherapies: From IgG catabolism, FCGRT gene polymorphisms, IVIg dosing and efficiency to specific FcRn inhibitors. Ther Adv Neurol Disord, 2021. 14: p. 1756286421997381.
200. Matthijs, G. and P. Marynen, A detetion polymorphism in the human alpha-2-macroglobulin (A2M) gene. Nucleic Acids Research, 1991. 19(18): p. 5102-5102.
201. Tcherkezian, J., et al., The human orthologue of CdGAP is a phosphoprotein and a GTPase-activating protein for Cdc42 and Rac1 but not RhoA. Biol Cell, 2006. 98(8): p. 445-56.
202. Li, K., et al., Identification and expression of a new type II transmembrane protein in human mast cells. Genomics, 2005. 86(1): p. 68-75.
203. Elomaa, O., et al., Structure of the human macrophage MARCO receptor and characterization of its bacteria-binding region. J Biol Chem, 1998. 273(8): p. 4530-8.
204. Launay, P., et al., TRPM4 is a Ca2+-activated nonselective cation channel mediating cell membrane depolarization. Cell, 2002. 109(3): p. 397-407.
205. Verlinden, L., et al., Nrp2 deficiency leads to trabecular bone loss and is accompanied by enhanced osteoclast and reduced osteoblast numbers. Bone, 2013. 55(2): p. 465-75.
206. Girard, B., et al., Human histamine N-methyltransferase pharmacogenetics: cloning and expression of kidney cDNA. Mol Pharmacol, 1994. 45(3): p. 461-8.
207. Katoh, M., WNT/PCP signaling pathway and human cancer (review). Oncol Rep, 2005. 14(6): p. 1583-8.
208. Dang, I., et al., The Arp2/3 inhibitory protein Arpin is dispensable for chemotaxis. Biol Cell, 2017. 109(4): p. 162-166.
209. Feng, T., et al., Generation of mucosal dendritic cells from bone marrow reveals a critical role of retinoic acid. J Immunol, 2010. 185(10): p. 5915-25.
210. Tambe, Y., et al., A novel apoptotic pathway induced by the drs tumor suppressor gene. Oncogene, 2004. 23(17): p. 2977-87.
211. Hase-Yamazaki, T. and Y. Aoki, Stimulation of human lymphocytes by cathepsin G. Cell Immunol, 1995. 160(1): p. 24-32.
212. van Kooyk, Y. and T.B. Geijtenbeek, A novel adhesion pathway that regulates dendritic cell trafficking and T cell interactions. Immunol Rev, 2002. 186: p. 47-56.
213. Stelzer, G., et al., The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analyses. Current Protocols in Bioinformatics, 2016. 54(1): p. 1.30.1-1.30.33.
214. Sarin, V., et al., Evaluating the efficacy of multiple myeloma cell lines as models for patient tumors via transcriptomic correlation analysis. Leukemia, 2020. 34(10): p. 2754-2765.
215. Maïga, S., et al., Paradoxical effect of lenalidomide on cytokine/growth factor profiles in multiple myeloma. British Journal of Cancer, 2013. 108(9): p. 1801-1806.
216. Xu, S., et al., Mesenchymal stem cells in multiple myeloma: a therapeutical tool or target? Leukemia, 2018. 32(7): p. 1500-1514.
217. Gu, Z., et al., Decreased Ferroportin Promotes Myeloma Cell Growth and Osteoclast Differentiation. Cancer Research, 2015. 75(11): p. 2211-2221.
218. Standal, T., et al., Osteopontin is an adhesive factor for myeloma cells and is found in increased levels in plasma from patients with multiple myeloma. Haematologica, 2004. 89(2): p. 174-82.
219. Colla, S., et al., Human myeloma cells express the bone regulating gene Runx2/Cbfa1 and produce osteopontin that is involved in angiogenesis in multiple myeloma patients. Leukemia, 2005. 19(12): p. 2166-76.
220. Pellagatti, A., et al., Lenalidomide inhibits the malignant clone and up-regulates the SPARC gene mapping to the commonly deleted region in 5q− syndrome patients. Proceedings of the National Academy of Sciences, 2007. 104(27): p. 11406-11411.
221. Cristobal, C.D., et al., Daam2 couples translocation and clustering of Wnt receptor signalosomes through Rac1. J Cell Sci, 2021. 134(2).
222. Zheng, H., et al., TREM2 Promotes Microglial Survival by Activating Wnt/β-Catenin Pathway. J Neurosci, 2017. 37(7): p. 1772-1784.
223. Koo, C.Z., et al., The tetraspanin Tspan15 is an essential subunit of an ADAM10 scissor complex. J Biol Chem, 2020. 295(36): p. 12822-12839.
224. Bonifer, C. and D.A. Hume, The transcriptional regulation of the Colony-Stimulating Factor 1 Receptor (csf1r) gene during hematopoiesis. FBL, 2008. 13(2): p. 549-560.
225. Wittrant, Y., et al., Colony-stimulating factor-1 (CSF-1) directly inhibits receptor activator of nuclear factor-{kappa}B ligand (RANKL) expression by osteoblasts. Endocrinology, 2009. 150(11): p. 4977-88.
226. Yamamoto, K., et al., Anti-inflammatory modulation of human myeloid-derived dendritic cell subsets by lenalidomide. Immunol Lett, 2019. 211: p. 41-48.
227. Galustian, C., et al., The anti-cancer agents lenalidomide and pomalidomide inhibit the proliferation and function of T regulatory cells. Cancer Immunol Immunother, 2009. 58(7): p. 1033-45.
228. Wu, L., et al., lenalidomide enhances natural killer cell and monocyte-mediated antibody-dependent cellular cytotoxicity of rituximab-treated CD20+ tumor cells. Clin Cancer Res, 2008. 14(14): p. 4650-7.
229. Zhytnik, L., et al., RNA sequencing analysis reveals increased expression of interferon signaling genes and dysregulation of bone metabolism affecting pathways in the whole blood of patients with osteogenesis imperfecta. BMC Medical Genomics, 2020. 13(1): p. 177.
230. Zhu, J., et al., Osteoblasts support B-lymphocyte commitment and differentiation from hematopoietic stem cells. Blood, 2007. 109(9): p. 3706-3712.
231. Li, B., et al., Impairment in Immunomodulatory Function of Mesenchymal Stem Cells from Multiple Myeloma Patients. Archives of Medical Research, 2010. 41(8): p. 623-633.
232. Taniwaki, M., et al., Elotuzumab for the Treatment of Relapsed or Refractory Multiple Myeloma, with Special Reference to its Modes of Action and SLAMF7 Signaling. Mediterr J Hematol Infect Dis, 2018. 10(1): p. e2018014.
233. De Salort, J., et al., Expression of SLAM (CD150) cell-surface receptors on human B-cell subsets: From pro-B to plasma cells. Immunology Letters, 2011. 134(2): p. 129-136.
234. Hsi, E.D., et al., CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma. Clin Cancer Res, 2008. 14(9): p. 2775-84.
235. Tai, Y.T., et al., Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu. Blood, 2008. 112(4): p. 1329-37.
236. Ritchie, D. and M. Colonna, Mechanisms of Action and Clinical Development of Elotuzumab. Clin Transl Sci, 2018. 11(3): p. 261-266.
237. Lonial, S., et al., Update on elotuzumab, a novel anti-SLAMF7 monoclonal antibody for the treatment of multiple myeloma. Expert Opin Biol Ther, 2016. 16(10): p. 1291-301.
238. Hsi, E.D., et al., CS1, a Potential New Therapeutic Antibody Target for the Treatment of Multiple Myeloma. Clinical Cancer Research, 2008. 14(9): p. 2775-2784.
239. Lu, Q., et al., Multiple myeloma: signaling pathways and targeted therapy. Mol Biomed, 2024. 5(1): p. 25.
240. Pene, F., et al., Role of the phosphatidylinositol 3-kinase/Akt and mTOR/P70S6-kinase pathways in the proliferation and apoptosis in multiple myeloma. Oncogene, 2002. 21(43): p. 6587-6597.
241. Shi, Y., et al., Signal pathways involved in activation of p70S6K and phosphorylation of 4E-BP1 following exposure of multiple myeloma tumor cells to interleukin-6. J Biol Chem, 2002. 277(18): p. 15712-20.
242. Maiso, P., et al., Defining the role of TORC1/2 in multiple myeloma. Blood, 2011. 118(26): p. 6860-70.
243. Raje, N., et al., Combination of the mTOR inhibitor rapamycin and CC-5013 has synergistic activity in multiple myeloma. Blood, 2004. 104(13): p. 4188-4193.
244. Felici, C., et al., Lenalidomide arrests cell cycle and modulates PD1-dependent downstream mTOR intracellular signals in melanoma cells. Melanoma Research, 2023. 33(5): p. 357-363.
245. Sancak, Y., et al., Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell, 2010. 141(2): p. 290-303.
246. Bar-Peled, L., et al., Ragulator Is a GEF for the Rag GTPases that Signal Amino Acid Levels to mTORC1. Cell, 2012. 150(6): p. 1196-1208.
247. Suragani, R.N.V.S., et al., Heme-regulated eIF2α kinase activated Atf4 signaling pathway in oxidative stress and erythropoiesis. Blood, 2012. 119(22): p. 5276-5284.
248. Chen, J.J. and S. Zhang, Heme-regulated eIF2α kinase in erythropoiesis and hemoglobinopathies. Blood, 2019. 134(20): p. 1697-1707.
249. Burwick, N., et al., The eIF2-alpha kinase HRI is a novel therapeutic target in multiple myeloma. Leukemia Research, 2017. 55: p. 23-32.
250. Shaughnessy, J., Amplification and overexpression of CKS1B at chromosome band 1q21 is associated with reduced levels of p27Kip1 and an aggressive clinical course in multiple myeloma. Hematology, 2005. 10 Suppl 1: p. 117-26.
251. Zhan, F., et al., CKS1B, overexpressed in aggressive disease, regulates multiple myeloma growth and survival through SKP2- and p27Kip1-dependent and -independent mechanisms. Blood, 2007. 109(11): p. 4995-5001.
252. Chen, G., et al., Ribosomal protein S3 mediates drug resistance of proteasome inhibitor: potential therapeutic application in multiple myeloma. Haematologica, 2024. 109(4): p. 1206-1219.
253. Nair, R., P. Gupta, and M. Shanmugam, Mitochondrial metabolic determinants of multiple myeloma growth, survival, and therapy efficacy. Front Oncol, 2022. 12: p. 1000106.
254. Steiner, N., et al., The metabolomic plasma profile of myeloma patients is considerably different from healthy subjects and reveals potential new therapeutic targets. PLoS One, 2018. 13(8): p. e0202045.
255. Camiolo, G., et al., Iron regulates myeloma cell/macrophage interaction and drives resistance to bortezomib. Redox Biol, 2020. 36: p. 101611.
256. Soriano, G.P., et al., Proteasome inhibitor-adapted myeloma cells are largely independent from proteasome activity and show complex proteomic changes, in particular in redox and energy metabolism. Leukemia, 2016. 30(11): p. 2198-2207. | |||||||
| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz | |||||||
| Fachbereich / Einrichtung: | Medizinische Fakultät » Institute » Institut für Pharmakologie und Klinische Pharmakologie | |||||||
| Dokument erstellt am: | 16.12.2025 | |||||||
| Dateien geändert am: | 16.12.2025 | |||||||
| Promotionsantrag am: | 04.09.2025 | |||||||
| Datum der Promotion: | 11.12.2025 |
