XPO1 E571 Mutations and Leukemogenesis in CLL
Posted: Wednesday, February 24, 2021
According to research presented in the Journal of Hematology & Oncology, patients with chronic lymphocytic leukemia (CLL) who have XPO1 mutations at E571 may experience increased pathogenesis. Rosa Lapalombella, PhD, of The Ohio State University, and colleagues found that “the mislocalization of intracellular machinery stemming from E571-XPO1 mutations may be priming preneoplastic B cells for complete leukemogenic transformation.”
The study included a multicenter, retrospective analysis of data from patients with CLL and murine research. Of the 1,286 patients with nonsynonymous XPO1 mutations included in the analysis, 72 had an E571K or E571G mutation. An association was noted between the presence of nonsynonymous mutations, high-risk genetic or epigenetic features, and accelerated disease progression.
A new mouse model with overexpression of wildtype or E571K/E571G-mutated XPO1 found in the B-cell compartment alone was created for this study. Known as Eµ-XPO1, this mouse model was crossed with the Eµ-TCL1 mouse model. Overexpression of wild-type or mutated XPO1 was observed to impact disease development in older mice. Mice with both mutated XPO1 B-cell expression and TCL1 experienced faster leukemogenesis than did Eµ-TCL1 mice. An evaluation of the crystal structures of E571- or E571K-XPO1 attached to selective inhibitors of nuclear export molecules (such as selinexor) may indicate that these molecules are potentially resistant to E571-XPO1 mutation.
“Despite these associations, the results of our study also confirm that the E571 XPO1 mutation does not impact survival outcomes in these patients, measured either in surrogate by time to first treatment or from time from diagnosis to death,” the stud authors commented.
Disclosure: For full disclosures of the study authors, visit jhoonline.biomedcentral.com.
