Abstract
BackgroundExportin 1 (XPO1/CRM1) is a key mediator of nuclear export with relevance to multiple cancers, including chronic lymphocytic leukemia (CLL). Whole exome sequencing has identified hot-spot somatic XPO1 point mutations which we found to disrupt highly conserved biophysical interactions in the NES-binding groove, conferring novel cargo-binding abilities and forcing cellular mis-localization of critical regulators. However, the pathogenic role played by change-in-function XPO1 mutations in CLL is not fully understood.MethodsWe performed a large, multi-center retrospective analysis of CLL cases (N = 1286) to correlate nonsynonymous mutations in XPO1 (predominantly E571K or E571G; n = 72) with genetic and epigenetic features contributing to the overall outcomes in these patients. We then established a mouse model with over-expression of wildtype (wt) or mutant (E571K or E571G) XPO1 restricted to the B cell compartment (Eµ-XPO1). Eµ-XPO1 mice were then crossed with the Eµ-TCL1 CLL mouse model. Lastly, we determined crystal structures of XPO1 (wt or E571K) bound to several selective inhibitors of nuclear export (SINE) molecules (KPT-185, KPT-330/Selinexor, and KPT-8602/Eltanexor).ResultsWe report that nonsynonymous mutations in XPO1 associate with high risk genetic and epigenetic features and accelerated CLL progression. Using the newly-generated Eµ-XPO1 mouse model, we found that constitutive B-cell over-expression of wt or mutant XPO1 could affect development of a CLL-like disease in aged mice. Furthermore, concurrent B-cell expression of XPO1 with E571K or E571G mutations and TCL1 accelerated the rate of leukemogenesis relative to that of Eµ-TCL1 mice. Lastly, crystal structures of E571 or E571K-XPO1 bound to SINEs, including Selinexor, are highly similar, suggesting that the activity of this class of compounds will not be affected by XPO1 mutations at E571 in patients with CLL.ConclusionsThese findings indicate that mutations in XPO1 at E571 can drive leukemogenesis by priming the pre-neoplastic lymphocytes for acquisition of additional genetic and epigenetic abnormalities that collectively result in neoplastic transformation.
Highlights
Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia in Western societies, characterized by clonal expansion of mature CD5+/CD19+ expressing B lymphocytes with significant genetic and clinical heterogeneity [1]
A total of 1286 samples were collected, those from The Mayo Clinic (Mayo; n = 248) contributing treatmentnaïve patients at diagnosis; samples collected from MD Anderson Cancer Center (MDACC; n = 367) were from treatment-naïve patients who subsequently required treatment; samples collected from The Ohio State University (OSU; n = 232) were from relapsed/refractory (R/R) patients receiving singleagent ibrutinib in clinical trials conducted at OSU; and samples collected from the chronic lymphocytic leukemia (CLL) Research Consortium
Recurrent Exportin 1 (XPO1) mutations E571K and E571G in CLL associate with poor prognosis Human XPO1 is a ~ 120 kDa protein comprised of 21 repetitive anti-parallel α-helical segments forming tertiary protein structures termed ‘HEAT domains’ (H1H21) [65,66,67]
Summary
Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia in Western societies, characterized by clonal expansion of mature CD5+/CD19+ expressing B lymphocytes with significant genetic and clinical heterogeneity [1]. Each class of drug yields extended remissions with variable time periods of treatment ranging from intermittent to continuous. Sequential treatment with these agents is effective. A subset of patients develop resistance to inhibitors of BCR pathways and BCL2 and have a relatively poor prognosis, spotlighting the need for further investigation of novel therapies [19]. Preventing this from occurring in high risk patients is important for which new therapies are needed. The pathogenic role played by change-in-function XPO1 mutations in CLL is not fully understood
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