Evaluation of ABC transporters in Leukemia

Projektleitung an der Vetmeduni

Grebien, Florian

Geldgeber

FWF Österreichischer Wissenschaftsfonds

Laufzeit

01.04.2022 - 31.03.2026

Abstract

Acute myeloid leukemia (AML) is an aggressive hematological disorder that is caused by aberrant proliferation of immature cells of the hematopoietic system. In addition to standard chemotherapy, several targeted therapies have been approved for the treatment of AML in recent years. Despite the overall success of these novel therapies, a significant number of patients is refractory and/or develops resistance against these drugs. Thus, a better molecular understanding of drug-naïve vs. drug-treated AML cells is needed to optimize the design of novel therapeutic strategies. The family of ATP-binding cassette (ABC) transporters comprises 48 transmembrane proteins that mediate transport of biomolecules and drugs across the cell membrane. They have been strongly implicated in chemotherapy resistance of cancer, including AML, but their function in normal AML physiology as well as in the context of novel targeted AML therapy is unknown. We hypothesize that beyond their function in chemotherapy resistance, ABC transporters act as important modulators of leukemia cell physiology and drug sensitivity. Using a combination of CRISPR/Cas9-enabled functional genomics, pharmacological and cell biological approaches in human AML cell lines, primary AML cells and mouse models, we will systematically evaluate the genetic requirements for ABC transporters in drug-naïve AML. Furthermore, we will analyze how ABC transporters modulate the sensitivity of bulk AML cells and Leukemia Stem Cells (LSC) to newly approved targeted treatments and investigate the contribution of ABC transporters to the development of resistance to targeted leukemia drugs.This work will be performed by a dedicated team of researchers, who will be embedded in a multidisciplinary group of experts in leukemia cell biology, functional genomics and bioinformatics. The project is also supported by world leading collaborators in the field of ABC transporter biology and targeted AML therapy. The results from this project will have several important implications that can be of immediate translational use. First, we will clarify the role of ABC transporters in normal AML physiology. Second, our work will reveal if ABC transporters hold potential for acting as novel biomarkers that can predict the efficacy of novel AML drugs. Thus, this work will reveal novel approaches, mechanisms, and factors that will help to improve the management of AML patients.