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Targeting the NRF2/HO-1 Antioxidant Pathway in FLT3-ITD-Positive AML Enhances Therapy Efficacy.

Authors
  • Kannan, Sankaranarayan1, 2
  • Irwin, Mary E1
  • Herbrich, Shelley M1, 3
  • Cheng, Tiewei1
  • Patterson, LaNisha L1
  • Aitken, Marisa J L1, 3
  • Bhalla, Kapil2
  • You, M James4
  • Konopleva, Marina2
  • Zweidler-McKay, Patrick A1, 3, 5
  • Chandra, Joya1, 3, 6
  • 1 Department of Pediatrics Research, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
  • 2 Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
  • 3 University of Texas MD Anderson UT Health Graduate School of Biomedical Sciences, Houston, TX 77004, USA.
  • 4 Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
  • 5 ImmunoGen, Waltham, MA 02451, USA.
  • 6 Epigenetics and Molecular Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Type
Published Article
Journal
Antioxidants
Publisher
MDPI AG
Publication Date
Apr 05, 2022
Volume
11
Issue
4
Identifiers
DOI: 10.3390/antiox11040717
PMID: 35453402
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Acute myeloid leukemia (AML) is a molecularly heterogenous hematological malignancy, with one of the most common mutations being internal tandem duplication (ITD) of the juxtamembrane domain of the fms-like tyrosine kinase receptor-3 (FLT3). Despite the development of FLT3-directed tyrosine kinase inhibitors (TKI), relapse and resistance are problematic, requiring improved strategies. In both patient samples and cell lines, FLT3-ITD raises levels of reactive oxygen species (ROS) and elicits an antioxidant response which is linked to chemoresistance broadly in AML. NF-E2-related factor 2 (NRF2) is a transcription factor regulating the antioxidant response including heme oxygenase -1 (HO-1), a heat shock protein implicated in AML resistance. Here, we demonstrate that HO-1 is elevated in FLT3-ITD-bearing cells compared to FLT3-wild type (WT). Transient knockdown or inhibitor-based suppression of HO-1 enhances vulnerability to the TKI, quizartinib, in both TKI-resistant and sensitive primary AML and cell line models. NRF2 suppression (genetically or pharmacologically using brusatol) results in decreased HO-1, suggesting that TKI-resistance is dependent on an active NRF2-driven pathway. In AML-patient derived xenograft (PDX) models, brusatol, in combination with daunorubicin, reduces leukemia burden and prolongs survival. Cumulatively, these data encourage further development of brusatol and NRF2 inhibition as components of combination therapy for refractory AML.

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