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Cancers (Basel). 2019 Dec 30;12(1). pii: E95. doi: 10.3390/cancers12010095.

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

Author information

1
Department of Biomedicine and Prevention, Tor Vergata University of Rome, 00133 Rome, Italy.
2
Neuro-Oncohematology Unit, Fondazione Santa Lucia, Istituto di Ricovero e Cura a Carattere Scientifico (I.R.C.C.S.), 00143 Rome, Italy.
3
Oncologia Medica, Policlinico Universitario Tor Vergata, 00133 Rome, Italy.
4
Istituto di Istologia ed Embriologia, Universita Cattolica del Sacro Cuore, 00168 Rome, Italy.
5
Fondazione Policlinico Universitario A. Gemelli, I.R.C.C.S., 00168 Rome, Italy.
6
Department of Anatomical, Histological, Forensic & Orthopedic Sciences, Sapienza University of Rome, laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, 00161 Rome, Italy.
7
Neuroimmunology and Flow Cytometry Units, Fondazione Santa Lucia I.R.C.C.S., 00143 Rome, Italy.

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.

KEYWORDS:

Ascorbate; HMOX1; NRF2; PML/RARa; ROS; acute promyelocytic leukemia

PMID:
31905996
DOI:
10.3390/cancers12010095
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