Nrf2 overexpression increases risk of high tumor mutation burden in acute myeloid leukemia by inhibiting MSH2

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Nuclear factor erythroid 2-related factor 2 (Nrf2) is implicated in cancer chemoresistance.
• The role of Nrf2 in tumor mutation burden and DNA mismatch repair (MMR) gene modulation in acute myeloid leukemia (AML) remains largely uncharacterized.

Purpose of the Study:

• To investigate the association between Nrf2 expression, tumor mutation burden, and drug resistance in AML.
• To elucidate the mechanism by which Nrf2 influences DNA mismatch repair and gene instability in AML.

Main Methods:

• Analysis of Nrf2 expression in AML patient samples.
• In vitro and in vivo studies assessing the impact of Nrf2 overexpression on cytarabine sensitivity, apoptosis, and drug resistance.
• Investigation of Nrf2's effect on MutS Homolog 2 (MSH2) protein expression and DNA MMR deficiency.
• Exploration of the role of reactive oxygen species (ROS) and JNK/c-Jun signaling in Nrf2-mediated MSH2 inhibition.

Main Results:

• Nrf2 overexpression in AML patients was linked to a higher frequency of gene mutations and increased drug resistance.
• Nrf2 overexpression conferred resistance to cytarabine-induced apoptosis in vitro and enhanced drug resistance in vivo.
• Nrf2 overexpression led to DNA MMR deficiency through the inhibition of MSH2 protein expression, independent of ROS.
• Activation of JNK/c-Jun signaling was identified as a mechanism by which Nrf2 inhibits MSH2 expression.

Conclusions:

• High Nrf2 expression is associated with gene instability-dependent drug resistance in AML.
• Nrf2 overexpression contributes to increased gene mutation frequency in AML by impairing DNA mismatch repair.
• Targeting Nrf2 or its downstream pathways may offer a novel therapeutic strategy for overcoming drug resistance in AML.