John Libbey Eurotext



Exportin 1 (or XPO1) abnormalities in hematological malignancies: from the gene to targeted therapy Volume 23, issue 1, Janvier-Février 2017


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1 Université de Normandie,
Unicaen, Caen, France
2 Université de Normandie,
Unirouen, Inserm U1245, Rouen, France
3 Département d’hématologie clinique,
centre Henri-Becquerel, Rouen, France
4 Université Paris Diderot,
CNRS, Institut de biologie physicochimique, laboratoire de biochimie théorique,
Paris, France
* Tirés à part

Exportin 1 (or XPO1) is a key regulatory protein essential for nuclear export. Quantitative and/or qualitative abnormalities of the XPO1 gene play a major role in the oncogenesis of several types of cancer including hematological malignancies. XPO1 could be therefore a key target for therapeutic strategies. The pharmacological inhibition of XPO1 is achieved by the use of specific inhibitors, named SINEs (selective inhibitor of nuclear export) which appear to be very effective in patients with several hematological diseases. We recently described that the XPO1 gene is targeted by a recurrent E571K mutation mainly observed in two types of lymphomas with clinical and phenotypic similarities: the primary mediastinal B-cell lymphoma (PMBL) and the classical Hodgkin's lymphoma (cHL). Because it is likely that the p.E571K XPO1 mutated form certainly plays a role in oncogenesis, it appears therefore essential to detect and quantify it. Using digital PCR (dPCR) and high-throughput sequencing (NGS) techniques, we also recently demonstrated the presence of the p.E571K variant in cell-free tumor DNA (cfDNA) from plasma of cHL/PMBL patients. The detection of this variant could be a useful tool for assessing the minimal residual disease (MRD). We present in this review a description of XPO1 protein, its functions, its molecular alterations, its interest as a biomarker. Finally, we report pre-clinical data on the use of SINEs in hematological lymphoid malignancies and current research on the development of new drugs targeting XPO1.