Phenformin, but not metformin, delays development of T-cell acute lymphoblastic leukemia/lymphoma via cell-autonomous AMPK activation

Diana Vara Ciruelos, Madhumita Dandapani, Fiona Russell, Katarzyna M. Grzes, Abdelmadjid Atrih, Marc Foretz, Benoit Viollet, Douglas Lamont, Doreen Cantrell, Grahame Hardie

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Abstract

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-1 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-1. 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 in vivo and in vitro. Thus, AMPK-1 can be a cell-autonomous tumor suppressor in the context of T-ALL, and phenformin may have potential for the prevention of some cancers.
Original languageEnglish
Pages (from-to)690-698.e4
JournalCell Reports
Volume27
Issue number3
DOIs
Publication statusPublished - 16 Apr 2019

Fingerprint

Phenformin
AMP-Activated Protein Kinases
T-cells
Metformin
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Chemical activation
T-Lymphocytes
Biguanides
Tumors
Neoplasms
Thymus
Growth
Thymus Gland
Oral Administration
Lymphoma
Stem Cells
Apoptosis

Keywords

  • AMP-activated protein kinase
  • AMPK
  • T cell acute lymphoblastic leukemia/lymphoma
  • T-ALL
  • biguanides
  • metformin
  • phenformin

Cite this

Vara Ciruelos, Diana ; Dandapani, Madhumita ; Russell, Fiona ; Grzes, Katarzyna M. ; Atrih, Abdelmadjid ; Foretz, Marc ; Viollet, Benoit ; Lamont, Douglas ; Cantrell, Doreen ; Hardie, Grahame. / Phenformin, but not metformin, delays development of T-cell acute lymphoblastic leukemia/lymphoma via cell-autonomous AMPK activation. In: Cell Reports. 2019 ; Vol. 27, No. 3. pp. 690-698.e4.
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abstract = "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-1 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-1. 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 in vivo and in vitro. Thus, AMPK-1 can be a cell-autonomous tumor suppressor in the context of T-ALL, and phenformin may have potential for the prevention of some cancers.",
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Phenformin, but not metformin, delays development of T-cell acute lymphoblastic leukemia/lymphoma via cell-autonomous AMPK activation. / Vara Ciruelos, Diana; Dandapani, Madhumita; Russell, Fiona; Grzes, Katarzyna M.; Atrih, Abdelmadjid; Foretz, Marc ; Viollet, Benoit; Lamont, Douglas; Cantrell, Doreen; Hardie, Grahame.

In: Cell Reports, Vol. 27, No. 3, 16.04.2019, p. 690-698.e4.

Research output: Contribution to journalArticle

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AU - Viollet, Benoit

AU - Lamont, Douglas

AU - Cantrell, Doreen

AU - Hardie, Grahame

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N2 - 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-1 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-1. 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 in vivo and in vitro. Thus, AMPK-1 can be a cell-autonomous tumor suppressor in the context of T-ALL, and phenformin may have potential for the prevention of some cancers.

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