Recurrent XPO1 mutations alter pathogenesis of chronic lymphocytic leukemia

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Exportin 1 (XPO1/CRM1) is crucial for nuclear export and implicated in various cancers, including chronic lymphocytic leukemia (CLL).
• Somatic XPO1 mutations identified via whole exome sequencing alter its function, affecting the localization of key regulators.
• The precise role of these gain-of-function XPO1 mutations in CLL pathogenesis remains unclear.

Purpose of the Study:

• To investigate the association between nonsynonymous XPO1 mutations and CLL progression.
• To establish and utilize a mouse model to study the impact of XPO1 mutations on B-cell malignancies.
• To determine the structural basis for the interaction of XPO1 mutations with selective nuclear export inhibitors (SINEs).

Main Methods:

• Retrospective analysis of 1286 CLL cases to correlate XPO1 mutations (E571K/G) with clinical and genetic features.
• Generation of a B-cell-specific XPO1 overexpression mouse model (Eµ-XPO1) and crossing with the Eµ-TCL1 CLL model.
• Determination of crystal structures of wild-type and mutant XPO1 (E571K) bound to SINEs (KPT-185, Selinexor, Eltanexor).

Main Results:

• Nonsynonymous XPO1 mutations were linked to high-risk genetic/epigenetic features and faster CLL progression.
• Constitutive B-cell overexpression of wild-type or mutant XPO1 in mice influenced CLL-like disease development.
• Concurrent expression of mutant XPO1 (E571K/G) and TCL1 accelerated leukemogenesis in the mouse model.
• Crystal structures revealed high similarity between wild-type and mutant XPO1 bound to SINEs, suggesting retained inhibitor efficacy.

Conclusions:

• XPO1 mutations at E571 can drive leukemogenesis by predisposing lymphocytes to further genetic/epigenetic alterations.
• These mutations prime cells for neoplastic transformation, highlighting XPO1's role in CLL development.
• The efficacy of SINEs, including Selinexor, is likely unaffected by E571 mutations in CLL patients.