Impact of activating NOTCH1 mutations on the pathogenesis of childhood precursor T-cell lymphoblastic leukemia (T-ALL)

Coordinator:    Prof. Dr. Andreas E. Kulozik
Institution: Universität Heidelberg,  Zentrum für Kinder- und Jugendmedizin Angelika-Lautenschläger-Klinik, Klinik für Kinderheilkunde III
The outcome of children with precursor T-cell acute lymphoblastic leukemia (T-ALL) has improved dramatically during the past 3 decades. Despite this progress, approximately 20% of patients develop recurrent disease, and the prognosis of relapsed ALL remains poor. Furthermore, surviving patients often experience significant toxicity. Therefore, individualized treatment strategies are warranted which improve survival in high-risk patients and decrease toxicity and late effects in standard-risk patients. Activating mutations of the NOTCH1 gene are common in childhood T-ALL. Our previous work established that activating NOTCH1 mutations significantly correlate with a good early treatment response and an exceptionally favorable long term outcome in children with T-ALL. In addition, microarray analysis revealed that specific gene expression signatures are indicative of the NOTCH1 mutational status and/or early treatment response. The first general aim of this project is to select differentially expressed genes from these prognostically relevant gene expression profiles (e.g. putative novel primary and secondary target genes of the NOTCH1 signaling pathway) and to functionally assess their role in the pathogenesis of T-ALL. In the second part of this project we will investigate functional links between NOTCH1 and microRNA (miRNA) expression and ask the important and topical question whether miRNAs can serve as prognostic biomarkers and whether differential miRNA expression contributes to the different molecular pathogenesis of NOTCH1-mutated and NOTCH1-non-mutated T-ALL. miRNAs as prognostically relevant biomarkers may be particularly valuable for those T-ALLs that lack NOTCH1 mutations and that would benefit from risk–adapted individualized therapy. Because miRNAs are frequently located at sites of genomic aberrations, we plan to identify small regions of genomic imbalances using array-CGH on DNA-microarrays and to correlate this information with clinically relevant prognostic markers and differentially expressed miRNAs. With its focus on childhood T-ALL and the integrative analysis of mRNA and miRNA expression profiles combined with array CGH studies this project contributes to the core of the overall goal of this network in that it aims at clinically and functionally relevant differences in RNA expression and genomic abnormalities in an important subtype of childhood leukemia.
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