Systematic Evaluation of ABC Transporters in Leukemia

Acute myeloid leukemia (AML) is an aggressive hematological disease caused by abnormal proliferation of immature cells of the hematopoietic system. In addition to standard chemotherapy, several targeted therapies have been recently approved for the treatment of AML. Despite the overall success of these novel therapies, a significant number of patients do not respond to treatment and/or develop resistance to these drugs. Therefore, a better molecular understanding of differences between therapy-nave and drug-treated AML cells is needed to optimize the design of new therapeutic strategies. The family of ATP-binding cassette (ABC) transporters comprises 48 transmembrane proteins that mediate the transport of biomolecules and drugs across the cell membrane. These proteins have been previously linked to cancer chemotherapy resistance. However, their function in AML cell physiology and in the context of novel targeted AML therapies 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-mediated functional genomics, pharmacological and cell biological approaches in human AML cell lines, primary AML cells and mouse models, we will systematically evaluate the role of ABC transporters in therapy-nave AML. In addition, we will analyze how ABC transporters modulate the sensitivity of AML cells and leukemia stem cells (LSCs) to newly approved targeted treatments. Finally, we will investigate the contribution of ABC transporters to the development of resistance to targeted leukemia drugs. The results of this project will be of immediate translational benefit. First, we will elucidate the role of ABC transporters in normal AML physiology. Second, our work will reveal whether ABC transporters have the potential to act as novel biomarkers that can predict the efficacy of novel AML drugs. Therefore, this work will provide novel approaches, mechanisms and factors that may contribute to improved management of AML patients.

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