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

Cell Rep. 2019 Apr 16;27(3):690-698.e4. doi: 10.1016/j.celrep.2019.03.067.


AMPK acts downstream of the tumor suppressor LKB1, yet its role in cancer has been controversial. AMPK is activated by biguanides, such as metformin and phenformin, and metformin use in diabetics has been associated with reduced cancer risk. However, whether this is mediated by cell-autonomous AMPK activation within tumor progenitor cells has been unclear. We report that T-cell-specific loss of AMPK-α1 caused accelerated growth of T cell acute lymphoblastic leukemia/lymphoma (T-ALL) induced by PTEN loss in thymic T cell progenitors. Oral administration of phenformin, but not metformin, delayed onset and growth of lymphomas, but only when T cells expressed AMPK-α1. This differential effect of biguanides correlated with detection of phenformin, but not metformin, in thymus. Phenformin also enhanced apoptosis in T-ALL cells both in vivo and in vitro. Thus, AMPK-α1 can be a cell-autonomous tumor suppressor in the context of T-ALL, and phenformin may have potential for the prevention of some cancers.

Keywords: AMP-activated protein kinase; AMPK; T cell acute lymphoblastic leukemia/lymphoma; T-ALL; biguanides; metformin; phenformin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / deficiency
  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism*
  • Administration, Oral
  • Animals
  • Cell Proliferation / drug effects*
  • Disease Models, Animal
  • Disease-Free Survival
  • Female
  • Glycolysis / drug effects
  • Hypoglycemic Agents / pharmacology*
  • Hypoglycemic Agents / therapeutic use
  • Male
  • Mechanistic Target of Rapamycin Complex 1 / antagonists & inhibitors
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Metformin / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • PTEN Phosphohydrolase / deficiency
  • PTEN Phosphohydrolase / genetics
  • Phenformin / pharmacology*
  • Phenformin / therapeutic use
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / mortality
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology*
  • Signal Transduction / drug effects*
  • Sirolimus / pharmacology


  • Hypoglycemic Agents
  • Metformin
  • Phenformin
  • Mechanistic Target of Rapamycin Complex 1
  • AMP-Activated Protein Kinases
  • PTEN Phosphohydrolase
  • Pten protein, mouse
  • Sirolimus