Dokument: The role of SLP65 in malignant transformation of human B cells.
| Titel: | The role of SLP65 in malignant transformation of human B cells. | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=3421 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20060615-001421-0 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Sprangers, Mieke [Autor] | |||||||
| Dateien: |
| |||||||
| Beitragende: | Prof. Dr. Müschen, Markus [Gutachter] Prof. Dr. Wunderlich, Frank [Gutachter] | |||||||
| Stichwörter: | SLP65, LYN, V(D)J Rekombination, Signaltransduktion, Leukämie, Lymphomen, B Zell Entwicklung, Ca2+ signaling, B Zell RezeptorSLP65, Lyn, V(D)J recombination, Ca2+ signaling, leukemia, lymphoma, B cell development, B cell receptor | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie | |||||||
| Beschreibungen: | B cell development is characterized by recombination of immunoglobulin heavy and light chain genes. Pro-B cells start rearranging their immunoglobulin V heavy chain genes. Human pre-B cells undergo apoptosis, unless they are rescued through survival signals of the pre-B cell receptor, which is expressed as a result of successful VH region gene rearrangement. After (pre-) B cell receptor activation, a number of signaling proteins are activated finally leading to a Ca2+ signal. One of the proteins involved in this cascade is the linker molecule SLP65. It is known that SLP65 expression is defective in a substantial fraction of cases of acute lymphoblastic leukemia. In addition, we also found defective expression of SLP65 in a fraction of cases of B cell lymphoma. Therefore, we investigated the consequences of SLP65-deficiency on (pre-) B cell receptor signal transduction in B cell lymphoproliferative diseases. We found that SLP65-deficient leukemia and lymphoma cells carry multiple IGHV region genes and also exhibit RAG1 and RAG2 expression together with ongoing V(D)J-recombinase activity. Reconstitution of SLP65-expression in SLP65-deficient leukemia and lymphoma cells results in downregulation of RAG1/2 expression and prevents both de novo VH-DJH rearrangements and secondary VH replacement. While SLP65 is essential for B cell receptor-induced Ca2+ mobilization in normal cells, B cell receptor engagement in SLP65-deficient as compared to SLP65-reconstituted B cell lymphoma cells resulted in an accelerated and enhanced yet short-lived Ca2+-signal. In a search for components of a SLP65-independent B cell receptor signaling pathway, we identified a critical interaction between the src-kinase LYN and PLC1. As shown by RNA interference, LYN is required for B cell receptor-induced Ca2+ release in SLP65-deficient but not in SLP65-reconstituted B cell lymphoma cells. LYN also transduced B cell receptor-dependent survival and proliferation signals including tyrosine-phosphorylation of STAT5 and MAPK1 in SLP65-deficient B cell lymphoma cells. We conclude that ongoing VH gene rearrangements are a frequent feature in B lymphoid malignancy which can be attributed to SLP65 in many cases. This function of SLP65 may have important implications for the clonal evolution of a SLP65-deficient leukemia or lymphoma because perpetual expression and activity of RAG proteins carries the risk of continuous DNA double-strand breaks and the accumulation of secondary transforming events in the leukemia and lymphoma cells. The aberrant signaling pathway in SLP65-deficient B cell lymphoma cells indicates that the src-kinase LYN can short-circuit B cell receptor signaling in SLP65-deficient B cell lymphoproliferation and thereby promote activation of survival and proliferation-related molecules.B cell development is characterized by recombination of immunoglobulin heavy and light chain genes. Pro-B cells start rearranging their immunoglobulin V heavy chain genes. Human pre-B cells undergo apoptosis, unless they are rescued through survival signals of the pre-B cell receptor, which is expressed as a result of successful VH region gene rearrangement. After (pre-) B cell receptor activation, a number of signaling proteins are activated finally leading to a Ca2+ signal. One of the proteins involved in this cascade is the linker molecule SLP65. It is known that SLP65 expression is defective in a substantial fraction of cases of acute lymphoblastic leukemia. In addition, we also found defective expression of SLP65 in a fraction of cases of B cell lymphoma. Therefore, we investigated the consequences of SLP65-deficiency on (pre-) B cell receptor signal transduction in B cell lymphoproliferative diseases. We found that SLP65-deficient leukemia and lymphoma cells carry multiple IGHV region genes and also exhibit RAG1 and RAG2 expression together with ongoing V(D)J-recombinase activity. Reconstitution of SLP65-expression in SLP65-deficient leukemia and lymphoma cells results in downregulation of RAG1/2 expression and prevents both de novo VH-DJH rearrangements and secondary VH replacement. While SLP65 is essential for B cell receptor-induced Ca2+ mobilization in normal cells, B cell receptor engagement in SLP65-deficient as compared to SLP65-reconstituted B cell lymphoma cells resulted in an accelerated and enhanced yet short-lived Ca2+-signal. In a search for components of a SLP65-independent B cell receptor signaling pathway, we identified a critical interaction between the src-kinase LYN and PLC1. As shown by RNA interference, LYN is required for B cell receptor-induced Ca2+ release in SLP65-deficient but not in SLP65-reconstituted B cell lymphoma cells. LYN also transduced B cell receptor-dependent survival and proliferation signals including tyrosine-phosphorylation of STAT5 and MAPK1 in SLP65-deficient B cell lymphoma cells. We conclude that ongoing VH gene rearrangements are a frequent feature in B lymphoid malignancy which can be attributed to SLP65 in many cases. This function of SLP65 may have important implications for the clonal evolution of a SLP65-deficient leukemia or lymphoma because perpetual expression and activity of RAG proteins carries the risk of continuous DNA double-strand breaks and the accumulation of secondary transforming events in the leukemia and lymphoma cells. The aberrant signaling pathway in SLP65-deficient B cell lymphoma cells indicates that the src-kinase LYN can short-circuit B cell receptor signaling in SLP65-deficient B cell lymphoproliferation and thereby promote activation of survival and proliferation-related molecules. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät » WE Biologie | |||||||
| Dokument erstellt am: | 15.06.2006 | |||||||
| Dateien geändert am: | 12.02.2007 | |||||||
| Promotionsantrag am: | 07.06.2006 | |||||||
| Datum der Promotion: | 07.06.2006 |
