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Università Degli Studi Di Milano the Role of NOTCH Pathway

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Università Degli Studi Di Milano the Role of NOTCH Pathway Università degli Studi di Milano PhD program in Experimental medicine and medical biotechnologies XXIX cycle The role of NOTCH pathway in multiple myeloma progression: control of IL-6 expression in malignant plasma cells and bone marrow niche PhD thesis: Serena GALLETTI R10586 Tutor: Professor Antonino NERI Academic Year: 2015/2016 Summary ABSTRACT ...................................................................................................................................................... 4 INTRODUCTION ............................................................................................................................................. 5 1. Multiple Myeloma ..................................................................................................................................... 6 1.1 Multiple Myeloma pathogenesis and progression ............................................................................. 6 1.2 Genetic of Multiple Myeloma ........................................................................................................... 9 1.3 Diagnosis and clinical features ........................................................................................................ 12 1.4 The role of bone marrow niche in MM ........................................................................................... 12 1.5 Pharmacological treatments of MM ................................................................................................ 16 2 NOTCH pathway ..................................................................................................................................... 18 2.1 NOTCH components structure ........................................................................................................ 18 2.1.1 NOTCH receptors structure ............................................................................................................ 18 2.1.2 NOTCH ligands structure ............................................................................................................... 20 2.2 Activation and intracellular signaling of NOTCH ........................................................................... 20 2.3 NOTCH pathway regulation ............................................................................................................ 22 2.3.1 Receptors regulation ....................................................................................................................... 22 2.3.2 Ligands regulation .......................................................................................................................... 24 2.4 NOTCH interaction with other signaling pathway .......................................................................... 26 2.4.1 Nuclear factor-κB ........................................................................................................................... 26 2.4.2 mTOR ............................................................................................................................................. 28 2.4.3 Phosphatidylinositol 3-kinase/AKT................................................................................................ 30 2.4.4 Epidermal growth factor receptor ................................................................................................... 31 2.4.5 Wnt pathway ................................................................................................................................... 32 2.4.6 Hedgehog pathway ......................................................................................................................... 33 2.5 NOTCH involvement in cancer disease .......................................................................................... 34 2.5.1 NOTCH in Multiple Myeloma ....................................................................................................... 38 3 Interleukin-6 pathway .............................................................................................................................. 40 3.1 IL-6 signaling ........................................................................................................................................ 41 3.2 IL-6 and cancers .................................................................................................................................... 42 3.2.1 IL-6 in Multiple Myeloma .............................................................................................................. 44 3.3. NOTCH pathway and IL-6 ................................................................................................................... 45 MATERIALS and METHODS ....................................................................................................................... 46 1. Cell cultures ............................................................................................................................................. 47 2. Treatments ............................................................................................................................................... 48 2.1 NOTCH pathway inhibition ............................................................................................................ 48 2.2 NOTCH pathway activation ............................................................................................................ 49 3. Gene expression analysis ......................................................................................................................... 49 3.1 RNA extraction ................................................................................................................................ 49 3.2 RNA quantification ......................................................................................................................... 50 3.3 Reverse transcription ....................................................................................................................... 50 3.4 Quantitative RT-PCR ...................................................................................................................... 51 3.5 Gene Expression Profiling (GEP) analysis ...................................................................................... 52 4. Western Blot ............................................................................................................................................ 53 5. RNA interference ..................................................................................................................................... 53 6. Luciferase reporter assay ......................................................................................................................... 54 7. Flow cytometry analysis .......................................................................................................................... 55 7.1 Apoptosis assay ............................................................................................................................... 55 7.2 Cell cycle assay ............................................................................................................................... 55 7.3 Intracellular IL-6 detection .............................................................................................................. 55 8. Immunohistochemistry (IHC).................................................................................................................. 56 9. Statistical analysis ................................................................................................................................... 57 RESULTS ........................................................................................................................................................ 58 1. Gene expression profiling (GEP) analysis on a cohort of MM patients .................................................. 59 2. IL-6 independence is a consequence of NOTCH pathway activity ......................................................... 61 3. IL-6 production is induced by NOTCH signaling in MM cells ............................................................... 66 4. BMSCs are able to support MM tumor growth through IL-6 production induced by NOTCH signaling pathway ........................................................................................................................................................... 70 5. NOTCH pathway activation in BMSCs mediated by JAGGED ligands presented on MM cells promotes IL-6 production by BMSCs and their ability to support tumor growth ........................................................... 74 6. NOTCH signaling withdrawal reduces the release of IL-6 in co-cultures of primary MM cells and BMSCs ............................................................................................................................................................ 78 CONCLUSIONS and DISCUSSION .............................................................................................................. 82 BIBLIOGRAPHY ........................................................................................................................................... 90 ABSTRACT Multiple myeloma (MM) is an incurable hematological tumor characterized by the accumulation of malignant plasma cells (PCs) within the bone marrow (BM). MM cells create a very strictly interaction with the surrounding BM niche that directly supports tumor growth through adhesion
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