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.
Highlights
Acute myeloid leukemias (AMLs) are clonal disorders of the hematopoietic system characterized by the rapid growth of abnormal precursors cells that interfere with normal hemopoiesis.Acute promyelocytic leukemia (APL) is a subtype of acute myeloide leukemia (AML) characterized by a reciprocal and balancedCancers 2020, 12, 95; doi:10.3390/cancers12010095 www.mdpi.com/journal/cancersCancers 2020, 12, 95 translocation involving retinoic acid receptor α (RARa) on chromosome 17 and promyelocytic leukemia (PML) on chromosome 15 which generates the oncogenic PML-RARα fusion protein
We found that acute promyelocytic leukemia (APL) blasts express NF-E2 p45-related factor 2 (NRF2) protein at a significantly lower level (0.6 ± 0.8, n = 8) than other AMLs samples (1.2 ± 0.4, n = 7) (p = 0.02) (Figure 1a)
NRF2 Transcriptional Activity Is Inhibited in APL Cells
Summary
Cancers 2020, 12, 95 translocation involving retinoic acid receptor α (RARa) on chromosome 17 and promyelocytic leukemia (PML) on chromosome 15 which generates the oncogenic PML-RARα fusion protein. Central in the pathogenesis of APL, PML/RARa impairs formation of functional PML nuclear bodies, and acts as a transcriptional repressor antagonizing myeloid differentiation, altering DNA repair and promoting the self-renewal capacity of APL-initiating cells [1,2,3,4]. NRF2 binds to antioxidant response elements (AREs) in the promoter region of genes involved in redox regulation, proteostasis, DNA repair, apoptosis, nutrient and xenobiotic metabolism [5,6,7,8,9,10,11]. A recent study showed that high-dose vitamin C selectively kills colon cancer cells carrying KRAS (KRAS proto-oncogene, GTPase) or BRAF (B-Raf proto-oncogene, serine/threonine kinase) mutations [14]
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