Iron chelation: an adjuvant therapy to target metabolism, growth and survival of murine PTEN-deficient T lymphoma and human T lymphoblastic leukemia/lymphoma

Abstract

Iron is an essential nutrient, acting as a catalyst for metabolic reactions that are fundamental to cell survival and proliferation. Iron complexed to transferrin is delivered to the metabolism after endocytosis via the CD71 surface receptor. We found that transformed cells from a murine PTEN-deficient T-cell lymphoma model and from T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/T-LL) cell lines overexpress CD71. As a consequence, the cells developed an addiction toward iron whose chelation by deferoxamine (DFO) dramatically affected their survival to induce apoptosis. Interestingly, DFO displayed synergistic activity with three ALL-specific drugs: dexamethasone, doxorubicin, and L-asparaginase. DFO appeared to act through a reactive oxygen species-dependent DNA damage response and potentiated the action of an inhibitor of the PARP pathway of DNA repair. Our results demonstrate that targeting iron metabolism could be an interesting adjuvant therapy for acute lymphoblastic leukemia.

Keywords:

• Iron metabolism
• addiction
• leukemia
• chemotherapy
• synergy

Acknowledgments

We are sincerely grateful to Ms Cendrine Dubaud regarding her expertise to maintain the mouse strains and assistance to generate the tPTEN-/- KO mice. We also thank the C3M Imaging Core Facility (Microscopy and Imaging Platform Côte d'Azur) and C3M animal room facility. Furthermore, we express thanks to Ms Chimène Morillon (Affymetrix analysis assistance) and to Dr. Ivan C. Moura for interesting discussions at the beginning of the project. The Centre Méditerranéen de Médecine Moléculaire (C3M) provided the financial support to perform the current research. We also thank the LiSA. ‘Lions Sport Action’ association and its President M Marc Infantes for financial help on this project. Célia Rosilio is a PhD fellowship recipient from La Ligue Nationale Contre le Cancer.

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article online at http://dx.doi.org/10.1080/10428194.2016.1239257.