Receptor protein-tyrosine phosphatases controlling activity of the oncoprotein FLT3 ITD

• Applicant: Professor Dr. Jörg P. Müller
• Subject Area: Cell Biology ; Hematology, Oncology
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 265483692

Receptor protein-tyrosine phosphatases controlling activity of the oncoprotein FLT3 ITDAcute Myeloid Leukemia (AML) is a heterogeneous group of diseases caused by combination of several genetic lesions. Mutations giving rise to the oncoprotein FLT3 ITD (Fms-like tyrosine kinase with internal tandem duplications) represent one of the important classes of driver mutations in a subset of 25-30% of patients. FLT3 is a class III receptor tyrosine kinase (RTK) which plays a role in cell survival, proliferation, and differentiation of haematopoietic progenitors of lymphoid and myeloid lineages. Mutant FLT3 ITD proteins exhibit an altered signalling and trafficking quality, which causally contribute to cell transformation. FLT3 ITD also drives production of reactive oxygen species (ROS). We have previously shown that the two transmembrane (receptor-like) protein-tyrosine phosphatases (RPTP) PTPRJ/DEP-1 and PTPRC/CD45 RPTP act as negative regulators of wild type FLT3 in vitro. Overlapping activity of both RPTP in vivo has previously also been observed in another context. In FLT3 ITD-transformed cells, PTPRJ/DEP-1 activity is partially compromised by ROS-mediated reversible oxidation. The aim of the proposed project is to assess in vivo the role of PTPRJ/DEP-1 and PTPRC/CD45 in regulating the transformation of myeloid cells by the AML-related oncoprotein FLT3 ITD using mouse models. The possibility to attenuate transformation by enhancing RPTP activity shall also be explored. For these aims, we will address the following specific goals:I) By using a previously established FLT3 ITD knock in- Ptprj knock out mouse strain, the effect of PTPRJ deficiency on FLT3 ITD-dependent transformation and the development of myeloproliferative disease shall be investigated.II) With the same strategy and technology, the effect of the relevant transmembrane PTP RPTPC/CD45, shall also be explored. Moreover, the effect of combined loss of both RPTP PTPRJ and PTPRC will be analyzed.III) We will use different techniques to enhance PTP activity of DEP-1, including the naturally occurring ligand TSP1, quenching PTP oxidation using ROS inactivating agents, and the genetic tool of CRISPR/Cas9-mediated genomic editing to explore PTP activation as novel strategy to combat FLT3 ITD-mediated transformation.Taken together, we expect a better understanding of the mechanism of negative control of FLT3 ITD-mediated transformation and novel insights into possible therapeutic approaches by enhancing PTP activity.

• DFG Programme: Research Grants