Recurrent mutations of the exportin 1 gene (XPO1) and their impact on selective inhibitor of nuclear export compounds sensitivity in primary mediastinal B‐cell lymphoma

Abstract

Primary mediastinal B-cell lymphoma (PMBL) is an entity of B-cell lymphoma distinct from the other molecular subtypes of diffuse large B-cell lymphoma (DLBCL). We investigated the prevalence, specificity, and clinical relevance of mutations of XPO1, which encodes a member of the karyopherin-b nuclear transporters, in a large cohort of PMBL. PMBL cases defined histologically or by gene expression profiling (GEP) were sequenced and the XPO1 mutational status was correlated to genetic and clinical characteristics. The XPO1 mutational status was also assessed in DLBCL, Hodgkin lymphoma (HL) and mediastinal gray-zone lymphoma (MGZL).The biological impact of the mutation on Selective Inhibitor of Nuclear Export (SINE) compounds (KPT-185/330) sensitivity was investigated in vitro. XPO1 mutations were present in 28/117 (24%) PMBL cases and in 5/19 (26%) HL cases but absent/rare in MGZL (0/20) or DLBCL (3/197). A higher prevalence (50%) of the recurrent codon 571 variant (p.E571K) was observed in GEP-defined PMBL and was associated with shorter PFS. Age, International Prognostic Index and bulky mass were similar in XPO1 mutant and wild-type cases. KPT-185 induced a dose-dependent decrease in cell proliferation and increased celldeath in PMBL cell lines harboring wild type or XPO1 E571K mutant alleles. Experiments in transfected U2OS cells further confirmed that the XPO1 E571K mutation does not have a drastic impact on KPT-330 binding. To conclude the XPO1 E571K mutation represents a genetic hallmark of the PMBL subtype and serves as a new relevant PMBL biomarker. SINE compounds appear active for both mutated and wild-type protein.

Nuclear export receptor CRM1 recognizes diverse conformations in nuclear export signals

“…Interestingly, Lys568 interacts electrostatically with Hs CRM1 Glu571, which is mutated to glycine or lysine in chronic lymphocytic leukemia and lymphomas with poor prognosis (Puente et al, 2011; Jardin et al, 2016; Camus et al, 2016). Disease mutations will abolish Glu571-Lys568 contacts and possibly affect NES binding and selectivity.…”

Diagnosis and classification of hematologic malignancies on the basis of genetics

“…120,122 Additionally, mutations in the nuclear export protein XPO1 were recently discovered in ;25% of both PMBL and cHL with much research going into the pathogenic mechanisms underlying this frequent alteration. 123 …”

Inhibition of nucleo-cytoplasmic shuttling through XPO1/CRM1: A unique therapeutic approach for treatment of haematological and solid malignancies

“…Interestingly, high frequency of XPO1 was observed in relapse CLL patient samples compared to untreated [19] . A high rate of XPO1 mutation (E571K) was also seen in primary mediastinal B-cell lymphoma (PMBL) [20] . XPO1 missense mutation has also been identified in esophageal squamous cell carcinoma [21] and thyroid cancer [22] .…”

“…Sequencing of PMBL samples showed recurrent hot-mutation (E571K) of XPO1. PMBL cell lines are sensitive to the SINE compound [20] . Verdinexor (KPT-335) has been approved by Food and Drug Administration for the treatment of non-Hodgkin lymphoma (NHL), osteosarcoma, mast cell tumor and melanoma in canines [48] .…”