RECURRENT XPO1 MUTATIONS IDENTIFIED AS PREDICTIVE MARKER FOR ADVANCED CLL PROGRESSION
Author(s): ,
Janek S. Walker
Affiliations:
Division of Hematology, Department of Internal Medicine,The Ohio State University,Columbus,United States;Biomedical Sciences Graduate Program,The Ohio State University,Columbus,United States
,
Zachary A. Hing
Affiliations:
Division of Hematology, Department of Internal Medicine,The Ohio State University,Columbus,United States;Medical Scientist Training Program,The Ohio State University,Columbus,United States
,
Bonnie Harrington
Affiliations:
Division of Hematology, Department of Internal Medicine,The Ohio State University,Columbus,United States;Department of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine,Michigan State University,East Lansing,United States
,
Christopher Oakes
Affiliations:
Division of Hematology, Department of Internal Medicine,The Ohio State University,Columbus,United States
,
Hatice Gulcin Ozer
Affiliations:
Department of Biomedical Informatics,The Ohio State University,Columbus,United States
,
Amy Lehman
Affiliations:
Center for Biostatistics,The Ohio State University,Columbus,United States
,
Jordan Skinner
Affiliations:
Division of Hematology, Department of Internal Medicine,The Ohio State University,Columbus,United States
,
Casey Cempre
Affiliations:
Division of Hematology, Department of Internal Medicine,The Ohio State University,Columbus,United States
,
Vincenzo Coppola
Affiliations:
Department of Molecular Virology, Immunology, and Medical Genetics, College of Medicine,The Ohio State University,Columbus,United States
,
John C. Byrd
Affiliations:
Division of Hematology, Department of Internal Medicine,The Ohio State University,Columbus,United States;Division of Medicinal Chemistry, College of Pharmacy,The Ohio State University,Columbus,United States
Rosa Lapalombella
Affiliations:
Division of Hematology, Department of Internal Medicine,The Ohio State University,Columbus,United States
EHA Library. Walker J. Jun 15, 2019; 266739; PS1122
Mr. Janek Walker
Mr. Janek Walker
Contributions
Abstract

Abstract: PS1122

Type: Poster Pitch

Presentation during EHA24: On Saturday, June 15, 2019 from 17:30 - 19:00

Location: Poster area

Background
Exportin 1 (XPO1/CRM1) is responsible for nuclear-to-cytosol export of RNAs and protein cargos, including various tumor suppressors (e.g. p53, IκB) and growth regulators (e.g. RB, p21). Our previous work has shown that XPO1 is upregulated in chronic lymphocytic leukemia (CLL), leading to mislocalization of critical cargos, which may contribute to activation of pathways involved in leukemogenesis and disease progression. Whole exome sequencing has revealed recurrent mutations to a highly conserved amino acid (E571G/E571K) near the XPO1 cargo binding groove in ~5% of CLL cases and in ~25% of CLL patients that develop a clinical complication of their disease with a very abysmal prognosis known as Richter’s transformation. Despite inherent association with advanced hematologic malignancies, conflicting reports describe the merit of XPO1 mutations as a predictive marker for poor clinical outcome in CLL.

Aims
We aimed to assess the significance of recurrent XPO1 E571 mutations on CLL progression and overall outcome by concurrent analysis of a human CLL clinical cohort and a large scale evaluation of a novel XPO1 transgenic mouse model.  

Methods
Retrospective analysis of an independent sample set of CLL cases (N=466) was used to correlate XPO1 mutation status (N=18, >30% clonal population CLL cells) with clinical data. These included time to first treatment, overall survival, IgHV mutation status, ZAP-70 expression (%), and status of epigenetic programming. Differential gene expression analysis in newly diagnosed untreated CLL patient lymphocytes was constructed from RNA-sequencing, with downstream pathway analysis performed by Ingenuity Pathway Analysis software. A novel XPO1 transgenic mouse model (Eµ-XPO1) was developed with human XPO1 (WT/G/K) gene under the heavy chain promoter/enhancer of the B cell expression, and was then crossed with the Eµ-TCL1 mouse to assess contribution of XPO1 mutations in concordance with murine CLL. Disease onset and progression was determined via flow cytometry (% CD19/CD5 double positive cells) analysis of peripheral blood. 

Results
In the CLL cohort we analyzed, presence of XPO1 E571 mutations (18/466, 4%) confers disease characteristics consistent with poor clinical prognosis; including association with low epigenetic programming (18/18), unmutated IgHV region (17/17), elevated ZAP-70 expression (p=0.012), and reduction in treatment free progression (p=0.002) and overall survival (p=0.068) compared with XPO1 un-mutated CLL. Similarly, overexpression of E571WT, K or G as the sole genetic abnormality (Eµ-XPO1) resulted in the development of lymphoid neoplasms at advanced ages (>20 mo) compared to age-matched B6 mice. Furthermore, overexpression of E571G (N=174, p=0.001) and E571K (N=188, p=0.093), but not E571WT (N=151, p=0.713) XPO1 showed a trend of accelerated disease onset in the Eµ-XPO1xTCL1 model consistent with a role of mutant XPO1 in disease progression. Lastly, RNA-seq in XPO1 E571 or wild-type CLL cells revealed unique clustering of differentially expressed genes specific to lymphocyte activation, signaling, and regulation, suggesting amplification of pro-survival and anti-apoptotic intracellular pathways.

Conclusion

We report evidence for XPO1 E571 mutations as a predictive marker for poor CLL clinical prognosis warranting further investigation for selective targeting of mutated XPO1 as a personalized cancer therapy in CLL.

Session topic: 5. Chronic lymphocytic leukemia and related disorders - Biology & Translational Research

Keyword(s): Animal model, B cell chronic lymphocytic leukemia, Expression profiling, Mutation analysis

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