Phenformin, But Not Metformin, Delays Development of T Cell Acute Lymphoblastic Leukemia/Lymphoma via Cell-Autonomous...

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• The role of AMP-activated protein kinase (AMPK) in cancer remains controversial, despite its activation by biguanides like metformin.
• Metformin use in diabetics is linked to reduced cancer risk, but the mechanism involving cell-autonomous AMPK activation in tumor progenitors is unclear.

Purpose of the Study:

• To investigate the cell-autonomous role of AMPK-α1 in T-cell acute lymphoblastic leukemia (T-ALL) development.
• To evaluate the efficacy of phenformin and metformin in a T-ALL mouse model.

Main Methods:

• Utilized a mouse model of T-ALL induced by PTEN loss in thymic T-cell progenitors with T-cell-specific AMPK-α1 deletion.
• Administered phenformin and metformin orally to assess their impact on lymphoma onset and growth.
• Measured biguanide levels in the thymus and assessed apoptosis in T-ALL cells in vivo and in vitro.

Main Results:

• Loss of AMPK-α1 accelerated T-ALL growth in PTEN-deficient mice.
• Phenformin, but not metformin, delayed lymphoma onset and growth, contingent on AMPK-α1 expression in T-cells.
• Phenformin was detected in the thymus, unlike metformin, and enhanced apoptosis in T-ALL cells.

Conclusions:

• AMPK-α1 functions as a cell-autonomous tumor suppressor in T-ALL.
• Phenformin demonstrates potential for T-ALL prevention and treatment by activating AMPK-α1, with differential tissue distribution compared to metformin.