PML/RARa interferes with NRF2 transcriptional activity increasing the sensitivity to ascorbate of acute promyelocytic leukemia cells

Cristina Banella, Gianfranco Catalano, Serena Travaglini, Mariadomenica Divona, Silvia Masciarelli, Gisella Guerrera, Francesco Fazi, Francesco Lo Coco, Maria Teresa Voso, Nelida Noguera

Research output: Contribution to journalArticlepeer-review

Abstract

NRF2 (NF-E2 p45-related factor 2) orchestrates cellular adaptive responses to stress. Its quantity and subcellular location is controlled through a complex network and its activity increases during redox perturbation, inflammation, growth factor stimulation, and energy fluxes. Even before all-trans retinoic acid (ATRA) treatment era it was a common experience that acute promyelocytic leukemia (APL) cells are highly sensitive to first line chemotherapy. Since we demonstrated how high doses of ascorbate (ASC) preferentially kill leukemic blast cells from APL patients, we aimed to define the underlying mechanism and found that promyelocytic leukemia/retinoic acid receptor α (PML/RARa) inhibits NRF2 function, impedes its transfer to the nucleus and enhances its degradation in the cytoplasm. Such loss of NRF2 function alters cell metabolism, demarcating APL tissue from both normal promyelocytes and other acute myeloide leukemia (AML) blast cells. Resistance to ATRA/arsenic trioxide (ATO) treatment is rare but grave and the metabolically-oriented treatment with high doses of ASC, which is highly effective on APL cells and harmless on normal hematopoietic stem cells (HSCs), could be of use in preventing clonal evolution and in rescuing APL-resistant patients.

Original languageEnglish
Article number95
JournalCancers
Volume12
Issue number1
DOIs
Publication statusE-pub ahead of print - Dec 30 2019

Keywords

  • Acute promyelocytic leukemia
  • Ascorbate
  • HMOX1
  • NRF2
  • PML/RARa
  • ROS

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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