Investigation to determine the role of the TCF/TLE family of transcription factors in stem cell self-renewal and differentiation in myeloid malignancies

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Dokumentart: Bachelor Thesis
Institut: Department Biotechnologie
Sprache: Englisch
Erstellungsjahr: 2015
Publikationsdatum:
SWD-Schlagwörter: Stammzelle
DDC-Sachgruppe: Biowissenschaften, Biologie

Kurzfassung auf Englisch:

Wnt signalling is very important in the maintenance of HSCs and abnormal Wnt signalling could be a reason for developing cancer. Wnt signalling activates the transcription of target genes, such as TCF/LEF, TLE, ICAT and RUNX1. However, it is not well known how altering the balance of these transcription factors increases self-renewal and suppresses differentiation and how in progressive CML-blast crisis and CMML the progenitors gain self-renewal potential. This study investigated the expression patterns of TCF/LEF, TLE, ICAT and RUNX1 genes in CML and CMML and determined which family members are important regulators of the canonical Wnt signalling pathway. Therefore, a blast crisis CML cell line (K562), which express the tyrosine kinase fusion protein BCR-ABL, and a murine ES cell line (E14tg2a) with inducible expression of the leukemic oncogene Tel/PDGFRβ (TP) were used. The basal levels of TCF/LEF, TLE, ICAT and RUNX1 genes were analysed in K562 and it was determined which family members of these genes are important regulators of the Wnt signalling through an activation and inhibition of the Wnt signalling pathway. E14tg2a were used to determine the alterations of these downstream genes when the oncogene TP was expressed because the oncogene caused haematopoietic differentiation and the preservation of self-renewal in this cell line. The findings indicate that TCF7, RUNX1, TCF4, TLE2 and TLE4 are important regulators of the Wnt signalling pathway and that the transcription factors TCF7, LEF1 and RUNX1 are highly expressed in K562 with and without an activation of the pathway. TCF7 and LEF1 were also highly expressed in E12tg2a cells; even the oncogene TP could not decrease the expression pattern. TCF7 and AML1 are important for self-renewal and pluripotency which confirm that myeloid progenitors in blast crisis CML and CMML gain self-renewal potential.

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