A33
Modulation of human JAK/STAT pathway signalling by functionally conserved regulators and their potential role in myeloid leukemia
Dhamayanthi Pugazhendhi, Patrick Muller, Martin Zeidler
University of Sheffield, Sheffield, South Yorkshire, UK
Background
Inappropriate activation of JAK/STAT signalling is well characterised in a number of human malignancies, including acute leukemia. The JAK/STAT pathway components have been evolutionary conserved and are present both in vertebrates and invertebrates. Whole genome RNAi screens in cultured Drosophila cells undertaken in our laboratory have identified a number of positive and negative pathway regulators.
Results
Here, we describe the analysis of 73 human genes representing homologues of 56 Drosophila genes we have previously identified as regulators of Drosophila JAK/STAT pathway. Using HeLa cells as a model, we examined the STAT1 target gene GBP1 to assay STAT1 activity and STAT3 target gene SOCS3 to assay STAT3 activity. The effect of 73 siRNAs on the cytokine induced GBP1 and SOCS3 target gene expression was analysed using real time QPCR.
Conclusions
The results have identified 58 previously unknown regulators of JAK/STAT pathway signalling, including a number showing differential regulation of STAT1 and STAT3. Some of the modulators identified have previously been implicated in various leukemias. The identification of leukemia associated genes as modulators of JAK/STAT signalling represents the first proposed mechanism of action for many of these proteins. Our latest data regarding their potential role as mitigators of leukemic transformation will be presented.
