Targeting nuclear import and export in hematological malignancies

Abstract

The transport of proteins across the nuclear membrane is a highly regulated process, essential for the cell function. This transport is actively mediated by members of the karyopherin family, termed importins, or exportins, depending on the direction of transport. These proteins play an active part in tumorigenesis, through aberrant localization of their cargoes, which include oncogenes, tumor-suppressor genes and mediators of key signal transduction pathways. Overexpression of importins and exportins is reported in many malignancies, with implications in cell growth and viability, differentiation, drug resistance, and tumor microenvironment. Given their broad significance across tumors and pathways, much effort is being put to develop specific inhibitors as a novel anticancer therapeutics. Already, selinexor, a specific inhibitor of exportin-1 (XPO1), is approved for clinical use. This review will focus on the role of importins and exportins in hematological malignancies. We will discuss current preclinical and clinical data on importins and exportins, and demonstrate how our growing understanding of their functions has identified new therapeutic targets.

Fig. 1. Simplified model of nuclear import with selected hallmark cancer cargo.

The importin α/β-cargo complex translocate into the nucleus through the NPC. In the nucleus, binding of abundant RanGTP mediates the release of the cargo. Gray text: hematological malignancies in which the nuclear transport of the specific cargo is shown to be significant. Star marks the binding site of the specified inhibitor in red. NLS nuclear localizing signal, NPC nuclear pore complex, DLBCL diffuse large B-cell lymphoma, APL acute promyelocytic leukemia, MM multiple myeloma, NHL non-Hodgkin lymphoma, CLL chronic lymphocytic leukemia.

Fig. 2. Simplified model of nuclear export with selected cargo of XPO1 XPO1 binds to cargoes bearing NES (nuclear export signal) with RanGTP to facilitate its active transport through the NPC.

In the cytoplasm and Ran GTPase-activating protein 1 (RanGAP1) mediates cargo release and RanGTP hydrolysis to RanGDP. The regulator of chromosome condensation 1 (RCC1) reforms RanGTP from RanGDP in the nucleus to maintain the gradient across the nuclear membrane. Star marks the binding site of the specified inhibitor in red. NPC nuclear pore complex.