Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the United States and is currently incurable. New tyrosine kinase inhibitors such as ibrutinib (BTK inhibitor) have shown very strong clinical responses. Despite this, they do not eradicate the malignant clone and resistance has emerged. Thus, combination strategies that target BTK are a high priority. Chromosome Region Maintenance 1 (CRM1/XPO1) is a nuclear export protein that shuttles tumor suppressor proteins such p53, I?B, and FoxO3a out of the nucleus, thereby preventing their anti-apoptotic and anti-proliferative function. XPO1 is overexpressed in many different solid and hematopoietic malignancies and is associated with poor prognosis and resistance to treatment. Our group has shown that inhibition of XPO1 by selective inhibitors of nuclear export (SINEs) is a promising therapeutic strategy in preclinical models of CLL and responses have been observed in ongoing clinical trials. Interestingly, XPO1 is recurrently mutated in CLL patients at a highly conserved residue in the cargo binding pocket. The function of this mutation remains unknown. We propose to determine the function of mutant and wild-type XPO1 and its role in CLL pathogenesis.
Our aims are 1) to determine the ability of mutant XPO1 to bind to target proteins and RNAs compared to wild-type, thereby establishing the functional significance of this disease associated mutation and 2) to overexpress mutant and wild-type XPO1 in a B cell specific manner in normal and leukemic mice, which will determine its role in leukemogenesis and CLL disease progression. Finally, we will 3) evaluate the dual inhibition of XPO1 and BTK (ibrutinib) as a relevant therapeutic strategy in CLL. Our long-term goals are to improve targeted therapies for CLL patients and to elucidate fundamental aspects of XPO1 biology that will have relevance to many other cancers.

Public Health Relevance

The goal of this proposal is to determine, for the first time, the function of a mutated protein that is associated with shorter survival in leukemia patients. We will obtain fundamental knowledge about the cancer causing ability of this protein, which will be valuable to other types of cancer as well.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Damico, Mark W
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Ohio State University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Hing, Z A; Fung, H Y J; Ranganathan, P et al. (2016) Next-generation XPO1 inhibitor shows improved efficacy and in vivo tolerability in hematological malignancies. Leukemia 30:2364-2372
Hing, Zachary A; Mantel, Rose; Beckwith, Kyle A et al. (2015) Selinexor is effective in acquired resistance to ibrutinib and synergizes with ibrutinib in chronic lymphocytic leukemia. Blood 125:3128-32