XPO1 in B cell hematological malignancies: from recurrent somatic mutations to targeted therapy

Vincent Camus (1) , Hadjer Miloudi (1) , Antoine Taly (2) , Brigitte Sola (1) , Fabrice Jardin (1)

1 GPMCND - Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques
2 LBT (UPR_9080) - Laboratoire de biochimie théorique [Paris]

Many recent publications highlight the large role of the pivotal eukaryotic nuclear export protein exportin-1 (XPO1) in the oncogenesis of several malignancies, and there is emerging evidence that XPO1 inhibition is a key target against cancer. The clinical validation of the pharmacological inhibition of XPO1 was recently achieved with the development of the selective inhibitor of nuclear export compounds, displaying an interesting anti-tumor activity in patients with massive pre-treated hematological malignancies. Recent reports have shown molecular alterations in the gene encoding XPO1 and showed a mutation hotspot (E571K) in the following two hematological malignancies with similar phenotypes and natural histories: primary mediastinal diffuse large B cell lymphoma and classical Hodgkin's lymphoma. Emerging evidence suggests that the mutant XPO1 E571K plays a role in carcinogenesis, and this variant is quantifiable in tumor and plasma cell-free DNA of patients using highly sensitive molecular biology techniques, such as digital PCR and next-generation sequencing. Therefore, it was proposed that the XPO1 E571K variant may serve as a minimal residual disease tool in this setting. To clarify and summarize the recent findings on the role of XPO1 in B cell hematological malignancies, we conducted a literature search to present the major publications establishing the landscape of XPO1 molecular alterations, their impact on the XPO1 protein, their interest as biomarkers, and investigations into the development of new XPO1-targeted therapies in B cell hematological malignancies.

Mots clés: XPO1; Exportin; Lymphoma; Targeted therapy; Minimal residual disease

Domaines: Sciences du Vivant [q-bio]

Vincent Camus, Hadjer Miloudi, Antoine Taly, Brigitte Sola, Fabrice Jardin. XPO1 in B cell hematological malignancies: from recurrent somatic mutations to targeted therapy. Journal of Hematology and Oncology, 2017, 10 (1), pp.515-519. ⟨10.1186/s13045-017-0412-4⟩. ⟨hal-02329725⟩