Recurrent XPO1 mutations alter pathogenesis of chronic lymphocytic leukemia

• DOI: 10.1186/s13045-021-01032-2
• Publication Date: 2021-01-15T10:03:05Z
• Authors: Janek S. Walker; Zachary A. Hing; Bonnie Harrington; Jordan Baumhardt; Hatice Gulcin Ozer; Amy Lehman; Brian Giacopelli; Larry Beaver; Katie Williams; Jordan N. Skinner; Casey B. Cempre; Qingxiang Sun; Sharon Shacham; Benjamin R. Strom...; Matthew K. Summers; Lynne V. Abruzzo; Laura Rassenti; Thomas J. Kipps; Sameer Parikh; Neil E. Kay; Kerry A. Rogers; Jennifer A. Woyach; Vincenzo Coppola; Yuh Min Chook; Christopher Oakes; John C. Byrd; Rosa Lapalombella
• Keywords: Male; Models, Molecular; Lymphoma; Cytoplasmic and Nuclear; Receptors, Cytoplasmic and Nuclear; Selinexor; Exportin 1 Protein; Cardiorespiratory Medicine and Haematology; Inbred C57BL; Sines; Epigenesis, Genetic; Mice; Models; Receptors; 2.1 Biological and endogenous factors; Chronic; RC254-282; Cancer; Leukemic; 0303 health sciences; Leukemia; Gene Expression Regulation, Leukemic; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Hematology; Lymphocytic; 3. Good health; Mutation analysis; XPO1; Female; 570; Lymphatic Research; Oncology and Carcinogenesis; 610; Karyopherins; Cardiovascular medicine and haematology; Mouse model; 03 medical and health sciences; Rare Diseases; Genetic; Genetics; Animals; Humans; Diseases of the blood and blood-forming organs; Expression profiling; Retrospective Studies; Biomedical and Clinical Sciences; Research; B-Cell; Molecular; Oncology and carcinogenesis; Leukemia, Lymphocytic, Chronic, B-Cell; Mice, Inbred C57BL; Gene Expression Regulation; Mutation; Chronic lymphocytic leukemia; RC633-647.5; Transcriptome; Epigenesis

AbstractBackgroundExportin 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 somaticXPO1point 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-functionXPO1mutations in CLL is not fully understood.MethodsWe performed a large, multi-center retrospective analysis of CLL cases (N = 1286) to correlate nonsynonymous mutations inXPO1(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)XPO1restricted 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 mutantXPO1could affect development of a CLL-like disease in aged mice. Furthermore, concurrent B-cell expression ofXPO1with E571K or E571G mutations andTCL1accelerated 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 byXPO1mutations at E571 in patients with CLL.ConclusionsThese findings indicate that mutations inXPO1at E571 can drive leukemogenesis by priming the pre-neoplastic lymphocytes for acquisition of additional genetic and epigenetic abnormalities that collectively result in neoplastic transformation.