|Titel:||Functional characterization of non-receptor tyrosine kinase dependent signal transduction in acute lymphoblastic leukemia of childhood||Sonstige Titel:||Funktionelle Charakterisierung von Nicht-Rezeptor Tyrosinkinase abhängiger Signaltransduktion in Akuter Lymphatischer Leukämie im Kindesalter||Sprache:||Englisch||Autor*in:||Pernudy Ubau, Allan Xavier||Erscheinungsdatum:||2013||Tag der mündlichen Prüfung:||2013-12-13||Zusammenfassung:||
The aim of this study was to assess the expression of protein tyrosine kinases (PTK) in acute lymphoblastic leukemia (ALL) patient samples at the protein level. Xenotransplanted primary ALL blasts and ALL cell lines were used as model system for the functional analysis of the role of PTK in ALL. The analysis revealed that Lyn, a member of the Src family kinase (SFK), was prominently expressed in a subgroup of ALL patient samples. To further investigate the biological consequence of elevated Lyn expression in ALL cells, Nalm6 and CALL3 cells were used as a model which recapitulated the high and low Lyn expression profile observed in patient specimens, respectively. Lyn is known to be associated with pre-BCR after receptor crosslinking. Analysis of the functional role of Lyn upon shRNA mediated Lyn repression and pre-BCR crosslinking showed that phosphorylation of downstream signaling proteins was strikingly reduced or delayed in Nalm6 cells. In addition, cell proliferation was substantially reduced in Nalm6 Lyn-knockdown cells. Conversely, an increase in the tyrosine phosphorylation was found in CALL3 Lyn-knockdown cells. Membrane microdomain, called lipid rafts, were shown to concentrate and regulate SFK111. However, data of the Lyn localization in the plasma membrane indicates that, whereas Lyn was exclusively present within defined lipid rafts in CALL3 cells, the protein was aberrantly localized all over the membrane in Nalm6 cells. The Lyn mislocalization was likely independent of lipid rafts and it could enable Lyn to interact with other proteins located outside rafts structures and promote its activation. Ultimately, preliminary data suggests that overexpression of Lyn is implicated in resistance to tyrosine kinase inhibitor (TKI) treatment.
Altogether these findings suggest that the high expression level and the abnormal subcellular distribution of Lyn allow it to escape from regulatory mechanisms only present in the lipid rafts. Thus, Lyn can cause an increase in the activation of downstream pathways and therefore might contribute to proliferation and possibly confer resistance to TKIs. In contrast, when Lyn was mainly present within the lipid rafts a negative regulation of downstream proteins was observed, pointing at a dual role for Lyn in the pathobiology of ALL.
|URL:||https://ediss.sub.uni-hamburg.de/handle/ediss/5250||URN:||urn:nbn:de:gbv:18-65625||Dokumenttyp:||Dissertation||Betreuer*in:||Horstmann, Martin (Prof. Dr)|
|Enthalten in den Sammlungen:||Elektronische Dissertationen und Habilitationen|
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