T-cell acute lymphoblastic leukemia (T-ALL) results from the uncontrolled proliferation of
immature T-cell precursors. Different possible genetic defects in oncogenes and tumor
suppressor genes have been identified to cooperate in T-ALL development. Oncogenic NOTCH1 activating mutations are of particular interest as they are found in more than 50% of
T-ALL cases marking NOTCH1 as an important therapeutic target. Recently, for a new class
of noncoding RNAs, so-called long noncoding RNAs (lncRNAs), evidence was obtained for a
role in cancer, but so far lncRNAs have not been studied in the context of T-ALL. In this
project we will further explore the regulatory networks governed by NOTCH1 in T-ALL by
identification of NOTCH1 regulated lncRNAs. Recently, we already demonstrated an important role for microRNAs (miRNAs) acting in miRNA-target gene networks in T-ALL development. Addressing the role of long noncoding RNAs in the context of NOTCH1 signaling in T-ALL is needed to expand the miRNA/mRNA regulatory networks governing T-ALL oncogenesis and to explore the putative role of lncRNAs in T-ALL. In addition, this research may provide new opportunities for development of NOTCH1 signaling based molecular treatment, thereby avoiding current toxicity problems arising with direct targeting of NOTCH1 through gamma-secretase inhibitors.