Inhibition of a new AXL isoform, AXL3, induces apoptosis of mantle cell lymphoma cells

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma with poor prognosis.
• There is a critical need for novel therapeutic strategies for MCL.
• The tyrosine kinase receptor AXL is implicated in various cancers.

Purpose of the Study:

• To identify and characterize novel AXL splice variants in MCL.
• To investigate the functional role of a newly identified AXL isoform (AXL3) in MCL pathogenesis.
• To evaluate the therapeutic potential of targeting AXL in MCL.

Main Methods:

• Identification and expression analysis of AXL splice variants in MCL cells.
• Functional characterization of AXL3 using CRISPR inhibition.
• Pharmacological inhibition of AXL signaling pathways.
• Preclinical evaluation of bemcentinib and ibrutinib in an MCL xenograft mouse model.

Main Results:

• A novel AXL splice variant, AXL3, lacking the ligand-binding domain, was identified and found to be constitutively activated in MCL cells.
• Knockdown of AXL3 induced apoptosis in MCL cells.
• Pharmacological inhibition of AXL decreased the activation of proproliferative and survival pathways (β-catenin, Akt, NF-κB).
• Bemcentinib demonstrated superior efficacy over ibrutinib in reducing tumor burden and improving overall survival in a preclinical MCL model.

Conclusions:

• AXL3 is a previously unidentified AXL splice variant crucial for MCL cell survival and proliferation.
• Targeting AXL, particularly the AXL3 isoform, represents a promising therapeutic strategy for MCL.
• Bemcentinib shows significant potential as a targeted therapy for mantle cell lymphoma.