RMRP-Induced Chemo-Resistance in Relapsed and Refractory Acute Myeloid Leukemia via Mitochondrial Dysfunction

Area of Science:

• Molecular Biology
• Cancer Biology
• Mitochondrial Biology

Background:

• Relapsed and refractory acute myeloid leukemia (R/R AML) presents a significant clinical challenge due to inherent chemotherapy resistance.
• Mitochondrial dysfunction is increasingly recognized as a key contributor to chemoresistance in AML.
• The specific role of the RNA component of mitochondrial RNA processing endoribonuclease (RMRP) in R/R AML pathogenesis and chemoresistance remains largely unelucidated.

Purpose of the Study:

• To investigate the role of RMRP in the context of chemotherapy resistance in R/R AML.
• To determine the impact of RMRP on mitochondrial function and transfer within the AML bone marrow microenvironment.

Main Methods:

• Utilized mass spectrometry to identify molecules associated with chemoresistance in AML.
• Assessed RMRP's role by examining its impact on mitochondrial transfer in AML models.
• Employed transmission electron microscopy and western blotting to analyze mitochondrial function and autophagy in RMRP-knockdown AML cells.

Main Results:

• RMRP was found to be overexpressed in R/R AML and its silencing sensitized AML cells to chemotherapy.
• RMRP knockdown led to decreased mitochondrial respiratory capacity, mtDNA copy numbers, and mitochondrial gene transcription.
• Further analysis revealed altered mitophagy markers, reduced mitochondrial methylation, and RMRP-TERT complex formation, indicating a role in post-transcriptional regulation.

Conclusions:

• High RMRP expression is significantly associated with mitochondrial dysfunction and chemotherapy resistance in R/R AML.
• These findings offer novel insights into the mechanisms of chemoresistance.
• Targeting RMRP presents a potential therapeutic strategy to overcome drug resistance in R/R AML.