Dokument: Pre-B cell receptor signaling prevents malignant transformation by BCR-ABL1
| Titel: | Pre-B cell receptor signaling prevents malignant transformation by BCR-ABL1 | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=8323 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20080711-095713-2 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Trageser, Daniel [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Müschen, Markus [Gutachter] Prof. Dr. Wunderlich, Frank [Gutachter] | |||||||
| Stichwörter: | pre-B cell receptor, BCR-ABL1, ALL | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie | |||||||
| Beschreibung: | The pre-B cell receptor plays a critical role in the early B cell development. As a failure of expression results in the lack of survival signal it represents an important checkpoint for further proliferation and differentiation. It has been shown that cells in acute lymphoblastic leukemia frequently carry defects in important pre-B cell receptor related signaling molecules like BTK or SLP65, indicating a tumor suppressive function. In contrast pre-B cell receptor expression is required in malignant lymphoproliferation and at least in mouse pre-B cells for transformation by the Myc oncogene. Therefore we investigated the role of the pre-B cell receptor as tumor suppressor vs. a requirement for leukemic transformation.
We found that only E2A-PBX1-mediated ALL carry a functional pre-B cell receptor and therefore seems to be essential for this type of leukemic transformation. The remaining investigated ALL subtypes are receptor independent or even show strong negative selection against a functional pre-B cell receptor. To clarify the role of the pre-B cell receptor during leukemogenesis, we studied the progressive transformation of pre-B cells in a transgenic mouse model for BCR-ABL1-induced ALL. Interestingly, before the onset of leukemia BCR-ABL1-transgenic pre-B cells respond normally to pre-B cell receptor engagement and express BCR-ABL1 at low levels. In full-blown leukemia, ALL cells do not respond to pre-B cell receptor engagement and express BCR-ABL1 at high levels. Signaling from the pre-B cell receptor and BCR-ABL1 are mutually exclusive: i) Treatment of leukemic mice with the BCR-ABL1 kinase inhibitor, AMN107, reinstates normal pre-B cell receptor signaling within seven days. ii) Reconstitution of pre-B cell receptor signaling in BCR-ABL1-transformed pre-B cells induces rapid cell death. iii) Transduction of human ALL cells with the BCR-ABL1 oncogene induces apoptosis in the presence of pre-B cell receptor signaling and accelerates proliferation in its absence. We conclude that pre-B cell receptor signaling -while compatible with expression of E2A-PBX1- renders B cell precursors non-permissive to transformation by BCR-ABL1 and likely other leukemogenic fusion genes. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät | |||||||
| Dokument erstellt am: | 04.07.2008 | |||||||
| Dateien geändert am: | 04.07.2008 | |||||||
| Promotionsantrag am: | 14.05.0008 | |||||||
| Datum der Promotion: | 08.07.0008 |
