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FTY720 increases CD74 expression and sensitizes mantle cell lymphoma cells to milatuzumab-mediated cell death
Lapo Alinari1, Emilia Mahoney, John Patton
1Division of Hematology, Department of Medicine, College of Medicine, The Ohio State University, Columbus, USA.
Abstract:
Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy with a short median survival despite multimodal therapy. FTY720, an immunosuppressive drug approved for the treatment of multiple sclerosis, promotes MCL cell death concurrent with down-modulation of phospho-Akt and cyclin D1 and subsequent cell-cycle arrest. However, the mechanism of FTY720-mediated MCL cell death remains to be fully clarified. In the present study, we show features of autophagy blockage by FTY720 treatment, including accumulation of autolysosomes and increased LC3-II and p62 levels. We also show that FTY720-induced cell death is mediated by lysosomal membrane permeabilization with subsequent translocation of lysosomal hydrolases to the cytosol. FTY720-mediated disruption of the autophagic-lysosomal pathway led to increased levels of CD74, a potential therapeutic target in MCL that is degraded in the lysosomal compartment. This finding provided rationale for examining combination therapy with FTY720 and milatuzumab, an anti-CD74 mAb. Treatment of MCL cell lines and primary tumor cells with FTY720 and milatuzumab resulted in statistically significant enhanced cell death, which was synergistic in blastic variant MCL cell lines. Significant in vivo therapeutic activity of combination treatment was also demonstrated in a preclinical, in vivo model of MCL. These findings support clinical evaluation of this combination in patients with MCL.
Insights
FTY720 induces mantle cell lymphoma (MCL) cell death by blocking autophagy and disrupting lysosomal function. Combining FTY720 with milatuzumab shows synergistic cell death and therapeutic activity in preclinical models.
Area of Science:
- Oncology
- Cell Biology
- Immunology
Background:
- Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy with poor prognosis.
- Current therapies offer limited long-term survival for MCL patients.
- The precise mechanism of FTY720's anti-cancer effects in MCL requires further elucidation.
Purpose of the Study:
- To investigate the mechanism of FTY720-induced cell death in MCL.
- To explore the potential of combining FTY720 with an anti-CD74 antibody, milatuzumab, for MCL treatment.
Main Methods:
- Analysis of autophagy markers (LC3-II, p62) and autolysosome accumulation in FTY720-treated MCL cells.
- Assessment of lysosomal membrane permeabilization and hydrolase release.
- Evaluation of combination therapy with FTY720 and milatuzumab in MCL cell lines, primary cells, and a preclinical in vivo model.
Main Results:
- FTY720 treatment blocked autophagy, increased autolysosome accumulation, and led to lysosomal membrane permeabilization.
- FTY720 disrupted the autophagic-lysosomal pathway, increasing CD74 levels.
- Combination therapy with FTY720 and milatuzumab demonstrated enhanced and synergistic cell death in MCL models, with significant in vivo therapeutic activity.
Conclusions:
- FTY720 induces MCL cell death through disruption of the autophagic-lysosomal pathway.
- Combination therapy of FTY720 and milatuzumab shows promising preclinical efficacy against MCL.
- This combination warrants clinical investigation for patients with mantle cell lymphoma.
