Deutsche Krebshilfe Frank-D. Böhmer
Interrupting the formation of reactive oxygen species as a therapeutic approach for the FLT3-ITD positive Acute Myeloid Leukemia.
The FLT3-ITD positive Acute Myeloid Leukemia has an unfavorable prognosis and novel therapeutic options are urgently required. Treatment with FLT3-ITD selective tyrosine kinase inhibitors (TKI) has recently emerged as a suitable therapeutic modality, however, 30-40% of patients still undergo relapse even after TKI therapy or allogeneic stem cell transplantation. Previous work of the applicants of this project has identified reactive oxygen species (ROS) as contributing to leukemic cell transformation by FLT3-ITD. Elevated ROS production is at least partially mediated by activation of signal transducer of transcription 5 (STAT5) and elevated expression of NADPH oxidase 4 (NOX4), which is a direct transcriptional target of STAT5. A consequence of ROS formation is the inactivation of protein-tyrosine phosphatases (PTP), among them DEP-1/PTPRJ, a negative regulator of FLT3-ITD signal transduction. NOX4 inhibition by genetic means or using NOX4-inhibiting compounds interrupts this pathway, restores PTP activity, and markedly attenuates proliferation of FLT3-ITD positive cells in vitro and the development of a leukemia-like disease in mouse models (Jayavelu et al., NOX4-driven ROS formation mediates PTP inactivation and cell transformation in FLT3ITD-positive AML cells. Leukemia. 2016, 30(2):473-83. Jayavelu et al., NOX-driven ROS formation in cell transformation of FLT3-ITD-positive AML. Exp Hematol. 2016, 44(12):1113-1122.).
Aim of the project is assessing the possibility of interfering with ROS formation as a novel therapeutic concept in FLT3-ITD positive AML.
1) The critical role of NOX-dependent ROS formation for generation and maintenance of FLT3-ITD positive AML shall be further validated.
2) The interruption of NOX-driven ROS formation shall be tested for efficiency in combination with the application of cytostatic agents and FLT3-ITD selective TKIs.
Involved people: Anne Kresinsky, Frank-D. Böhmer in cooperation with Muhammed Burak Demircan, Florian Heidel (Abteilung Hämatologie und Internistische Onkologie des UKJ)
Grant Support: Deutsche Krebshilfe, 2017 - 2020