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Titel
Bioinformatics analyses of transcriptional and translational profiling in acute lymphoblastic leukemia (ALL) : translational control by glucocorticoids ; molecular basis of anti-leukemic effect of glucocorticoids ; role of miR-125B, CASP2 and PIDD1 in lymphomagenesis / Tatsiana Aneichyk
VerfasserAneichyk, Tatsiana
Begutachter / BegutachterinGeley, Stephan ; Trajanoski, Zlatko
GutachterKofler, Reinhard
Erschienen2015
Umfang157 Bl. : Ill., graph. Darst.
HochschulschriftInnsbruck, Med. Univ., Diss., 2015
Anmerkung
Enth. u.a. 2 Veröff. d. Verf. aus den Jahren 2013 - 2015
Datum der AbgabeJuni 2015
SpracheEnglisch
Bibl. ReferenzOeBB
DokumenttypDissertation
Schlagwörter (DE)acute lymphoblastic leukemia / translational profiling / transcriptional profiling / glucocorticoids / lymphomagenesis
Schlagwörter (EN)acute lymphoblastic leukemia / translational profiling / transcriptional profiling / glucocorticoids / lymphomagenesis
Schlagwörter (GND)Akute lymphatische Leukämie / Glucocorticosteroide / Microarray / Genexpression
URNurn:nbn:at:at-ubi:1-3104 Persistent Identifier (URN)
Zugriffsbeschränkung
 Das Werk ist frei verfügbar
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Bioinformatics analyses of transcriptional and translational profiling in acute lymphoblastic leukemia (ALL) [19.31 mb]
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Zusammenfassung (Deutsch)

Lymphoid malignancies present a broad spectrum of cancers derived from lymphocytes, and acute lymphoblastic leukemia (ALL) is the most frequent type of cancer diagnosed in children. Current research in pathobiology of these malignancies is focusing on understanding the role of frequent genetic alterations and gene products that arise thereof in terms of their effect on cell proliferation, differentiation and survival. Glucocorticoids (GCs) are known to cause cell cycle arrest and cell death in some normal and malignant lymphoblasts. For that reason GCs are included in essentially all chemotherapy protocols applied in the treatment of lymphoid malignancies, including childhood ALL (chALL). GCs act mainly via regulating gene transcription, although GC control of mRNA translation has also been reported but has never been assessed systematically.

In the first part of my thesis, I analyzed possible effects of GC on the translational efficiency of expressed genes in two chALL model systems employing technique called “translational profiling”. My analyses did not reveal significant differences in translational efficiency of expressed genes thereby arguing against a potential regulatory effect of GCs on translation at least in the investigated systems.

In the second part of my thesis I investigated transcriptional effects of GC in vivo using microarray data from 46 patients undergoing GC systemic monotherapy and available clinical information, e.g. molecular subtype of ALL and reduction in peripheral blood lymhoblasts. Transcriptional regulation by GC was studied using a number of bioinformatics approaches such as differential gene expression and gene ontology analyses. Further, I combined microarray data with clinical information using classical regression models in order to identify genes whose expression or GC regulation might correlate with clinical response, and applied elastic-net regularization to address combinatorial effects of gene expression and regulation. These analyses revealed that, although there are a number of common response genes, the transcriptional response to GC in vivo varies considerably in the different molecular sub-types of this disease. Regarding the anti-leukemic response, repression of mRNA for key regulators of G2/M transition was commonly observed in all sub-types whereas I failed to observe a common transcriptional control of apoptotic genes. The data suggests that GC-induced cell death does not result from transcriptional regulation of the apoptotic machinery itself but rather might result from a widespread deregulation of gene expression.

The final part of this thesis describes two collaborative studies where potential candidates in lymphoma- and leukemia-genesis were investigated using several mouse models. I performed microarray based gene expression profiling to identify potential effectors of the key candidates (miR125b, CASP2 and PIDD1), and/or verify the obtained results by analyzing publicly available data.

Zusammenfassung (Englisch)

Lymphoid malignancies present a broad spectrum of cancers derived from lymphocytes, and acute lymphoblastic leukemia (ALL) is the most frequent type of cancer diagnosed in children. Current research in pathobiology of these malignancies is focusing on understanding the role of frequent genetic alterations and gene products that arise thereof in terms of their effect on cell proliferation, differentiation and survival. Glucocorticoids (GCs) are known to cause cell cycle arrest and cell death in some normal and malignant lymphoblasts. For that reason GCs are included in essentially all chemotherapy protocols applied in the treatment of lymphoid malignancies, including childhood ALL (chALL). GCs act mainly via regulating gene transcription, although GC control of mRNA translation has also been reported but has never been assessed systematically.

In the first part of my thesis, I analyzed possible effects of GC on the translational efficiency of expressed genes in two chALL model systems employing technique called “translational profiling”. My analyses did not reveal significant differences in translational efficiency of expressed genes thereby arguing against a potential regulatory effect of GCs on translation at least in the investigated systems.

In the second part of my thesis I investigated transcriptional effects of GC in vivo using microarray data from 46 patients undergoing GC systemic monotherapy and available clinical information, e.g. molecular subtype of ALL and reduction in peripheral blood lymhoblasts. Transcriptional regulation by GC was studied using a number of bioinformatics approaches such as differential gene expression and gene ontology analyses. Further, I combined microarray data with clinical information using classical regression models in order to identify genes whose expression or GC regulation might correlate with clinical response, and applied elastic-net regularization to address combinatorial effects of gene expression and regulation. These analyses revealed that, although there are a number of common response genes, the transcriptional response to GC in vivo varies considerably in the different molecular sub-types of this disease. Regarding the anti-leukemic response, repression of mRNA for key regulators of G2/M transition was commonly observed in all sub-types whereas I failed to observe a common transcriptional control of apoptotic genes. The data suggests that GC-induced cell death does not result from transcriptional regulation of the apoptotic machinery itself but rather might result from a widespread deregulation of gene expression.

The final part of this thesis describes two collaborative studies where potential candidates in lymphoma- and leukemia-genesis were investigated using several mouse models. I performed microarray based gene expression profiling to identify potential effectors of the key candidates (miR125b, CASP2 and PIDD1), and/or verify the obtained results by analyzing publicly available data.