Multidrug resistance protein 4/ ATP binding cassette transporter 4: a new potential therapeutic target for acute myeloid leukemia.

Sabrina Copsel,Victoria Wargon,Frans G.M Russel,Ariana Bruzzone,Maria May,Jeannette Cany,Carina Shayo,Carlos Davio,Julien Beyrath

doi:10.18632/oncotarget.2425

Abstract

Less than a third of adults patients with acute myeloid leukemia (AML) are cured by current treatments, emphasizing the need for new approaches to therapy. We previously demonstrated that besides playing a role in drug-resistant leukemia cell lines, multidrug resistance protein 4 (MRP4/ABCC4) regulates leukemia cell proliferation and differentiation through the endogenous MRP4/ABCC4 substrate, cAMP. Here, we studied the role of MRP4/ABCC4 in tumor progression in a mouse xenograft model and in leukemic stem cells (LSCs) differentiation. We found a decrease in the mitotic index and an increase in the apoptotic index associated with the inhibition of tumor growth when mice were treated with rolipram (PDE4 inhibitor) and/or probenecid (MRPs inhibitor). Genetic silencing and pharmacologic inhibition of MRP4 reduced tumor growth. Furthermore, MRP4 knockdown induced cell cycle arrest and apoptosis in vivo. Interestingly, when LSC population was isolated, we observed that increased cAMP levels and MRP4/ABCC4 blockade resulted in LSCs differentiation. Taken together, our findings show that MRP4/ABCC4 has a relevant role in tumor growth and apoptosis and in the eradication of LSCs, providing the basis for a novel promising target in AML therapy.

Highlights

Acute myeloid leukemia (AML) is a heterogeneous clonal disorder where early hematopoietic cells fail to differentiate and do not undergo programmed cell death or apoptosis
Results so far indicate that MRP4 is involved in tumor growth and apoptosis, suggesting that MRP4 might be a new target for AML treatment
Current evidences suggest that MRP4/ABCC4 is implicated in chemotherapy resistance, and in cancer biology

Summary

Introduction

Acute myeloid leukemia (AML) is a heterogeneous clonal disorder where early hematopoietic cells fail to differentiate and do not undergo programmed cell death or apoptosis. The study of multidrug resistance proteins (MRPs), known as members of the C-family of ATP-binding cassette (ABC) drug transporters, was classically focused on their role in cancer chemotherapy, on their ability to confer clinical drug resistance [4]. While several members of the ABC family are established as drug transporters, others mediate transport of intracellular substances that have relevant functions in cancer biology [5]. MRP4/ABCC4 is the main transporter for cAMP, a relevant signaling molecule that controls cellular proliferation, differentiation, and apoptosis, especially in hematopoietic development [6,7,8]. Comparison of different AML subtypes showed that the highest level of MRP4/ABCC4 is expressed in the least differentiated subtypes [10]

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