Metabolic pathways and chemotherapy resistance in acute myeloid leukemia (AML): Insights into Enoyl-CoA hydratase domain-containing protein 3 (<i>ECHDC3</i>) as a potential therapeutic target.
ECHDC3 knockdown significantly affects mitochondrial function and metabolism in AML, but the clinical implications for chemotherapy resistance require further investigation.
Where it sits
this study against the rest of the ara 290 corpusSummary and findings
This study investigates the role of enoyl-CoA hydratase domain-containing protein 3 (ECHDC3) in chemotherapy resistance in acute myeloid leukemia (AML). The researchers utilized siRNA knockdown of ECHDC3 and performed various assessments including RNA sequencing and metabolomic analysis. Significant changes in mitochondrial function and metabolic pathways were observed, particularly in the context of chemotherapy sensitivity.
Abstract
<h4>Background</h4>Acute myeloid leukemia (AML) is characterized by high relapse and mortality rates. Our previous investigation identified enoyl-CoA hydratase domain-containing protein 3 (<i>ECHDC3</i>) as being of prognostic significance in AML; however, the underlying pathways remain elusive. The intricate crosstalk among genetic abnormalities, metabolic pathways, and protein dysfunctions underpins the complexity contributing to its poor prognosis.<h4>Methods</h4><i>ECHDC3</i> was knocked down by siRNA and subjected to RNA sequencing, chromatin immunoprecipitation (ChIP), and metabolomic assessments. Cell culture media were subjected to metabolomic assessments to evaluate changes in the bone marrow microenvironment. Mass spectrometry was conducted on bone marrow leukemia stem cells (CD34<sup>+</sup>) from chemotherapy-sensitive (S) and chemotherapy-resistant (R) patients. Additionally, untargeted metabolomic sequencing was performed on bone marrow supernatants from this patient cohort, and a combined proteomic-metabolomic analysis was conducted on the sequencing results from paired samples.<h4>Results</h4>Knockdown of <i>ECHDC3</i> significantly reduced the mitochondrial membrane potential (<i>p</i> < 0.0001), increased the mitochondrial DNA (mtDNA) copy number <i>MT-CO1</i> (<i>p</i> = 0.0367) and <i>MT-CO2</i> (<i>p</i> = 0.0081), and enhanced manganese superoxide dismutase (MnSOD) activity (<i>p</i> = 0.0003). Significant differences were observed in choline metabolism in cancer (<i>p</i> = 0.0063), linoleic acid metabolism (<i>p</i> = 0.0160), and alpha-linolenic acid metabolism (<i>p</i> = 0.0250) between the R and S groups. Furthermore, correlation analysis of proteomic and metabolomic data suggested that choline and glycerophospholipid metabolism may play pivotal roles in the development of chemotherapy resistance in AML.<h4>Conclusions</h4><i>ECHDC3</i> contributes to chemotherapy resistance in AML by regulating mitochondrial function, autophagy, and metabolic pathways. This study highlights <i>ECHDC3</i> as a potential therapeutic target and offers insights into the development of AML treatments to overcome drug resistance.