Vitamin A Resistenz in derakuten myeloischen Leukämie: Die Rolle des nukleären Repressors Ski undfunktionelle shRNA Barcode Screens in myeloischen Zellen

Coordinator:    Prof. Dr. Andreas Neubauer
Institution: Phillips-Universität Marburg
Acute myeloid leukemia (AML) is a disease of hematopoeitic progenitor cells with high lethality. Beside age, cytogenetic aberrations are the most important prognostic markers. AML with monosomy 7 or deletion of chromosome 7q (-7/del7q) has a very bad prognosis. We showed that in this AML subtype the expression of the nuclear oncogene Ski is highly upregulated and identified Ski as an repressor of retinoic acid (ATRA) induced myeloid differentiation (Ritter et al, Leukemia 2006). Especially AML patients with low Ski expression in their blasts treated with chemotherapy and additionally ATRA showed a trend towards longer relapse free survial (Teichler et al, Haematologica 2008). We also found that loss of a regulatory mi(cro)R(NA), miR29a located on chromosome 7q32 is one reason for upregulation of Ski in -7/del7q AML patients (Teichler et al, Blood 2011). Furthermore we demonstrated that the Ski expression is regulated by the oncogenic myeloid transcription factor c-Myb. Moreover we observed that primary AML patient cells with high Ski expression showed apoptosis and/or cellular differentiation after treatment with histone deacetylase inhibitors (HDACi) in vitro. In parallel HDACi induces a Ski specific ubiquitinylation enzyme that decreases Ski by proteasomal degradation. The aim of our project is to find new therapy options for AML because older patients are often refractory to conventional chemotherapy. AML with mutation within the tyrosine kinase FLT3 (FLT3-ITD) belongs to the AML subgroups with unfavourable outcome. We found that the multikinase inhibitor Sorafenib is an effective alternative for treatment of refractory FLT3-ITD positive AML patients before or after allogeneic stem cell transplantation (Metzelder et al, Blood 2009, Metzelder et al, Leukemia 2012). We revealed that AML patients with FLT3-ITD mutation have higher Ski levels than cells without this mutation. Treatment of FLT3-ITD positive cells with Sorafenib reduced Ski expression compared to cells without mutation. Therefore the combined treatment with HDACi and the multikinase inhibitor Sorafenib could be a new option for a more successful AML therapy. 
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