Inhibition of NRF2 signaling overcomes acquired resistance to arsenic trioxide in FLT3-mutated Acute Myeloid Leukemia.
Title | Inhibition of NRF2 signaling overcomes acquired resistance to arsenic trioxide in FLT3-mutated Acute Myeloid Leukemia. |
Publication Type | Journal Article |
Year of Publication | 2024 |
Authors | Jebanesan DZechariah, Illangeswaran RStephen St, Rajamani BM, Vidhyadharan RThalayattu, Das S, Bijukumar NK, Balakrishnan B, Mathews V, Velayudhan SR, Balasubramanian P |
Journal | Ann Hematol |
Volume | 103 |
Issue | 6 |
Pagination | 1919-1929 |
Date Published | 2024 Jun |
ISSN | 1432-0584 |
Keywords | Animals, Arsenic Trioxide, Cell Line, Tumor, Drug Resistance, Neoplasm, Female, fms-Like Tyrosine Kinase 3, Humans, Leukemia, Myeloid, Acute, Mice, Mutation, NF-E2-Related Factor 2, Signal Transduction, Xenograft Model Antitumor Assays |
Abstract | De novo acute myeloid leukemia (AML) patients with FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD) have worse treatment outcomes. Arsenic trioxide (ATO) used in the treatment of acute promyelocytic leukemia (APL) has been reported to be effective in degrading the FLT3 protein in AML cell lines and sensitizing non-APL AML patient samples in-vitro. We have previously reported that primary cells from FLT3-ITD mutated AML patients were sensitive to ATO in-vitro compared to other non-M3 AML and molecular/pharmacological inhibition of NF-E2 related factor 2 (NRF2), a master regulator of antioxidant response improved the chemosensitivity to ATO and daunorubicin even in non FLT3-ITD mutated cell lines and primary samples. We examined the effects of molecular/pharmacological suppression of NRF2 on acquired ATO resistance in the FLT3-ITD mutant AML cell line (MV4-11-ATO-R). ATO-R cells showed increased NRF2 expression, nuclear localization, and upregulation of bonafide NRF2 targets. Molecular inhibition of NRF2 in this resistant cell line improved ATO sensitivity in vitro. Digoxin treatment lowered p-AKT expression, abrogating nuclear NRF2 localization and sensitizing cells to ATO. However, digoxin and ATO did not sensitize non-ITD AML cell line THP1 with high NRF2 expression. Digoxin decreased leukemic burden and prolonged survival in MV4-11 ATO-R xenograft mice. We establish that altering NRF2 expression may reverse acquired ATO resistance in FLT3-ITD AML. |
DOI | 10.1007/s00277-024-05742-8 |
Alternate Journal | Ann Hematol |
PubMed ID | 38630133 |
PubMed Central ID | 5777239 |
Grant List | EMR/2017/003880 / / Department of Science and Technology, Government of Rajasthan / CRG/2021/004281 / / Department of Science and Technology, Government of Rajasthan / |