Recurrent XPO1 mutations alter pathogenesis of chronic lymphocytic leukemia
| Autor: | Zachary A. Hing, Jennifer A. Woyach, Katie Williams, Kerry A. Rogers, Brian Giacopelli, Neil E. Kay, Jordan M. Baumhardt, Matthew K. Summers, Benjamin R. Stromberg, Sameer A. Parikh, Sharon Shacham, Janek S. Walker, Christopher C. Oakes, Rosa Lapalombella, Vincenzo Coppola, Thomas J. Kipps, Qingxiang Sun, Bonnie K. Harrington, Hatice Gulcin Ozer, Larry Beaver, Laura Z. Rassenti, Amy Lehman, Jordan N. Skinner, Yuh Min Chook, Casey Cempre, Lynne V. Abruzzo, John C. Byrd |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Nonsynonymous substitution
Male Models Molecular Cancer Research Lymphoma Cytoplasmic and Nuclear Chronic lymphocytic leukemia Mutant Receptors Cytoplasmic and Nuclear Selinexor Cardiorespiratory Medicine and Haematology Inbred C57BL Sines Epigenesis Genetic Mice Models Receptors 2.1 Biological and endogenous factors Chronic Aetiology Cancer Leukemic Leukemia Gene Expression Regulation Leukemic Hematology lcsh:Diseases of the blood and blood-forming organs lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Lymphocytic Mutation analysis Oncology XPO1 Female Oncology and Carcinogenesis Biology Karyopherins lcsh:RC254-282 Mouse model Rare Diseases Genetic Genetics medicine Animals Humans Neoplastic transformation Epigenetics Molecular Biology Expression profiling Retrospective Studies lcsh:RC633-647.5 Point mutation Research B-Cell Wild type Molecular medicine.disease Leukemia Lymphocytic Chronic B-Cell Mice Inbred C57BL Gene Expression Regulation Mutation Cancer research Transcriptome Epigenesis |
| Zdroj: | Journal of Hematology & Oncology Journal of Hematology & Oncology, Vol 14, Iss 1, Pp 1-21 (2021) Journal of hematology & oncology, vol 14, iss 1 |
| ISSN: | 1756-8722 |
| Popis: | 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 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. |
| Databáze: | OpenAIRE |
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