Role of SIRT7 in FLT3 ITD driven cell differentiation and transformation

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Oncogenic ITD mutations in the receptor tyrosine kinase FLT3 represent one of the important classes of driver mutations in Acute Myeloid Leukemia (AML) patients. Despite approval of Midostaurin as inhibitor of this oncogene, FLT3 ITD positive AML patients are still associated with poor prognosis. The function of FLT3 in promoting myeloid development remains poorly defined, despite being commonly mutated in AML. Defining differentiation pathways is central to understand pathogenesis of this hematopoietic disorder. Our preparatory work indicates for the first time a molecular correlation of FLT3 ITD-based development of myeloid neoplasms to the expression of SIRT7 as factor controlling HSC quiescence.The basis of this project application are our novel findings about the role of SIRT7 in myeloid stem-cell disorders, which were recently published in Leukemia (Kaiser et al., 2020). Our work established SIRT7 as important factor in the development of age-dependent myeloid stem-cell disorders and therefore changes of SIRT7 expression as a relevant pathomechanism in FLT3 ITD-positive AML cells. AML patients with low SIRT7 have poor prognosis demonstrating clinical relevance of this protein for patient survival. SIRT7 was recently identified as factor regulating hematopoietic stem cell (HSC) quiescence and aging. Molecular alterations within the hematopoietic system influence cellular longevity and differentiation. The aim of this proposed project is to dissect the mechanism, how FLT3 ITD mutations induce cell differentiation by affecting SIRT7 expression and thereby driving accumulation of myeloid expansion of blast cells in vivo. By using primary AML patient samples, established in vitro model cell systems and mouse models we will study the role of SIRT7 on FLT3 ITD-mediated myeloid aberrancies and clonal expansion. After establishing molecular correlation of FLT3 ITD-SIRT7-signalling on HSC differentiation/ transformation rejuvenation strategies of HSC (i. e. SIRT7 activation) will be envisaged. This could in the future allow to control FLT3 ITD-mediated imbalances of HSC quiescence and subsequently suppression of myeloid differentiation FLT3 ITD AML patients. Working hypotheses- SIRT7 is reduced in AML (FLT3 ITD) cells (cell lines, primary samples, mouse BM cells)- Suppression of SIRT7 in FLT3 ITD kinase activity dependent- C/EBP-mediated control of SIRT7 expression is negatively regulated by FLT3 ITD- Restoration of SIRT7 induces cell differentiation and suppresses cell transformationObjectivesi) Characterize the role of FLT3 ITD on SIRT7 activityii) Analyse the mechanism, how SIRT7 mediates FLT3 ITD-driven cell transformation/ cell differentiation on cellular leveliii) Assess function of SIRT7 on FLT3 ITD-driven cell transformation/ hematopoietic differentiation in vivoiv) Affecting FLT3 ITD mediated cell transformation by activation of the cellular protein acetylation