2013 - 2021
Targeting STAT5-regulated Transcription in Myeloid Neoplasms.
The project part leader, Richard Moriggl, is Deputy Speaker of this SFB and is Director of the Ludwig Boltzmann Institute for Cancer Research (LBI-CR) in Vienna. He is a basic cancer researcher and has a major interest and focus in STAT5 expression and function in hematopoietic neoplasms, including CML. During the past few years, Richard has developed concepts to convert or block oncogenic STAT5 in leukemic cells. In addition, the group was able to show that STAT5 forms oncogenic tetramers, and is expressed and exhibits specific functions in both the nuclear and cytoplasmic compartment of leukemic cells. In the current project the deputy speaker and his team study the expression, role, and function of STAT5 in JAK2-mutated MPN and Ph+ CML, with the major aim to identify druggable sites on STAT5 and to block STAT5-functions through site-specific targeting approaches.
The project employs various mouse models and also studies primary human MPN/CML cells and LSC in defined SFB collaborations. The aims of project #07 are to explore the mechanisms and consequences of drug-induced ablation of STAT5 activity in MPN cells; to establish preclinical in vitro and in vivo datasets for STAT5 inhibitors as a basis for the development of Phase I clinical trials; and to identify most potent drug partners that synergize with STAT5 inhibitors. Further aims are to test and validate the effects of various STAT5 inhibitors on pYSTAT5 expression, growth, and survival of primary CD34+/CD38− LSC in BCR-ABL1+ CML and JAK2 V617F+ MPN together with #02 and #04, as well as to evaluate combinatorial drug action with pharmacoscopy, a new technology developed by #11.
Project #07 contributes substantially to the common goal of the SFB for several reasons: The team of #07 has vast expertise in establishing and analyzing mouse models in leukemia research, with particular know-how in JAK-STAT pathway analyses. We will share all tools and MPN mouse models on a collaborative basis with all SFB F47 groups. We integrated the JAK2 V617F MPN mouse model with graded STAT5 expression into SFB F47 and we also collaborated with #02 and #10 to establish CALR-transgenic MPN models with graded pYSTAT5. Our labs are well equipped and staffed for histopathology support and genetic manipulation of primary cells, with viral transduction, and xenotransplantation facilities. Daily routine lab research analysis and examination of core cancer pathways is ongoing in our labs. The team of #07 will support all SFB groups with histopathology and immunostaining analysis in MPN models. Our lab is an established center of excellence in mouse histopathology and analysis of hematopoietic cancer models. We provide equipment for digital image quantification and state-of-the art diagnostics to SFB F47 partners #02, #04, #06, #10, and #11. They will benefit from our broad expertise in analysing BM and other organs in mice.
Finally, the project part leader supports the SFB as Deputy Speaker. All in all, project #07 is essential and will guarantee that the aims in this SFB can be reached.