PML/RARa Interferes with NRF2 Transcriptional Activity Increasing the Sensitivity to Ascorbate of Acute Promyelocytic Leukemia Cells.

Cancers (Basel) 2019 Dec 30;12(1). Epub 2019 Dec 30.

Department of Biomedicine and Prevention, Tor Vergata University of Rome, 00133 Rome, Italy.

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.

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12010095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016898PMC
December 2019

Publication Analysis

Top Keywords

acute promyelocytic
8
apl cells
8
blast cells
8
promyelocytic leukemia
8
nrf2 function
8
high doses
8
cells
6
acid receptor
4
receptor pml/rara
4
pml/rara inhibits
4
leukemia/retinoic acid
4
promyelocytic leukemia/retinoic
4
underlying mechanism
4
mechanism promyelocytic
4
inhibits nrf2
4
common experience
4
enhances degradation
4
degradation cytoplasm
4
cytoplasm loss
4
nucleus enhances
4

Similar Publications