Siebolts, Udo (2011). New aspects into pathophysiology and molecular diagnostics of myeloproliferative neoplasms. PhD thesis, Universität zu Köln.
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Abstract
The Philadelphia chromosome negative myeloproliferative neoplasms (MPN) comprise diverse entities of hematopoetic stem cell disorders with hematopoetic stem cell transplantation as the only curative therapeutic option. A collective finding of some subgroups is the activating point mutation of JAK2 p.V617F, important for diagnosis and detection of minimal residual disease (MRD) but a rather late event in the course of MPN. In this study, we first focused on characteristics of the neoplastic peripheral blood CD34- positive stem cell fraction. Thus, we could reveal a characteristic aberrant morphology and phenotype, and performing cDNA- array analysis most notably an imbalance of DNA- dependent protein kinase subunits which may contribute to the accumulation of chromosomal aberrations, accumulation of hematopoetic cell, and prolongation of CD34- positive peripheral blood stem cells life span (Wickenhauser, Perez, et al. 2003; Siebolts, Breuhahn, et al. 2009). Moreover, there is evidence of a distinct, non-neoplastic, CD34- positive peripheral blood stem cell population which may offer perspectives in treatment of the diseases (Siebolts, Ates, et al. 2005). The CD34- positive stem cell fraction, as the underlying source of the malignancy, is of course of particular importance, not only for understanding of the pathophysiological process but also for understanding of relapse and regenerative incidents. Performing fluorescence in situ hybridization on bone marrow biopsies, we found an almost complete chimerism following stem cell transplantation concerning the differentiated hematopoesis, whereas CD34- positive cells remained of recipient origin to a higher proportion (Thiele, Varus, et al. 2007; Siebolts, Thiele, et al. 2008). Since hematopoetic stem cell transplantation, especially after invention of reduced intensity conditioning (RIC) is a feasible curative option for an increasing number of MPN patients, reliable detection of the specific JAK2 p.V617F mutation as a sign of minimal residual disease (MRD) becomes more and more important. Therefore, we created in combination of a robust QPCR with a wild- type blocking PCR, a powerful tool for reliable detection of MRD in these patients (Siebolts, Lange, et al. 2010). Future prospects of MPN research will also focus on the newly-discovered field of non-coding RNA. Therefore, we tested the possibility to perform further retrospective analysis on easily accessible paraffin embedded formalin fixed tissue, and could show for the first time that extraction of sufficient amount of miRNA, with subsequent expression analysis is possible even after decalcification and also after decades (Siebolts, Varnholt, et al. 2009).
Item Type: | Thesis (PhD thesis) | ||||||||
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Corporate Contributors: | ZMMK | ||||||||
URN: | urn:nbn:de:hbz:38-46001 | ||||||||
Date: | 21 December 2011 | ||||||||
Language: | English | ||||||||
Faculty: | Faculty of Mathematics and Natural Sciences | ||||||||
Divisions: | Ehemalige Fakultäten, Institute, Seminare > Faculty of Mathematics and Natural Sciences > no entry | ||||||||
Subjects: | Natural sciences and mathematics Medical sciences Medicine |
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Date of oral exam: | 21 December 2011 | ||||||||
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Refereed: | Yes | ||||||||
URI: | http://kups.ub.uni-koeln.de/id/eprint/4600 |
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