Kurzfassung

FLT3 internal tandem duplications (FLT3-ITD) are among the most common genetic alterations in acute myeloid leukemia (AML). Several FLT3 tyrosine kinase inhibitors (TKI) are currently evaluated in clinical trials. Clinical responses are typically transient due to the emergence of TKI resistant leukemic clones. To improve FLT3 TKI therapy, it will be critical to avoid or overcome drug resistance. Besides leukemia cell-intrinsic factors, such as secondary mutations in the FLT3 tyrosine kinase...FLT3 internal tandem duplications (FLT3-ITD) are among the most common genetic alterations in acute myeloid leukemia (AML). Several FLT3 tyrosine kinase inhibitors (TKI) are currently evaluated in clinical trials. Clinical responses are typically transient due to the emergence of TKI resistant leukemic clones. To improve FLT3 TKI therapy, it will be critical to avoid or overcome drug resistance. Besides leukemia cell-intrinsic factors, such as secondary mutations in the FLT3 tyrosine kinase domain, resistance can be mediated by surrounding stromal cells. Preliminary data indicate that targeting of FLT3-ITD-positive cells eradicates cycling leukemic blasts, but not cells that are embedded in their niche in the bone marrow. The goal of this PhD project proposal is to identify cellular pathways that are involved in stroma-mediated drug resistance. To this end we established an in vitro model of FLT3-ITD leukemia cells co-cultured with stroma cells. We will apply global gene expression analysis and a genome-wide CRISPR/Cas9 knockout screen in order to identify key cellular components involved in stroma-mediated drug resistance. Candidates will be verified in independent experiments and evaluated further in vitro and in vivo. The overall goal of these studies is to identify and validate promising target molecules that can be moved forward into early clinical trials.
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