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Published on: September 30, 2015
Multi-omics reveals mitochondrial metabolism proteins susceptible for drug discovery in AML
Mika Caplan1,2, Karli J Wittorf1,2, Kasidy K Weber1,2
1Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA.
Abstract:
Acute myeloid leukemia (AML) is a devastating cancer affecting the hematopoietic system. Previous research has relied on RNA sequencing and microarray techniques to study the downstream effects of genomic alterations. While these studies have proven efficacious, they fail to capture the changes that occur at the proteomic level. To interrogate the effect of protein expression alterations in AML, we performed a quantitative mass spectrometry in parallel with RNAseq analysis using AML mouse models. These combined results identified 34 proteins whose expression was upregulated in AML tumors, but strikingly, were unaltered at the transcriptional level. Here we focus on mitochondrial electron transfer proteins ETFA and ETFB. Silencing of ETFA and ETFB led to increased mitochondrial activity, mitochondrial stress, and apoptosis in AML cells, but had little to no effect on normal human CD34+ cells. These studies identify a set of proteins that have not previously been associated with leukemia and may ultimately serve as potential targets for therapeutic manipulation to hinder AML progression and help contribute to our understanding of the disease.
Insights
This study reveals novel protein targets in acute myeloid leukemia (AML). Researchers found specific mitochondrial proteins, ETFA and ETFB, that, when silenced, induce cancer cell death without harming healthy cells, offering new therapeutic avenues.
Area of Science:
- Hematology
- Cancer Biology
- Proteomics
Background:
- Acute myeloid leukemia (AML) research traditionally uses RNA sequencing, missing proteomic changes.
- Understanding protein expression is crucial for deciphering AML pathogenesis.
- Genomic alterations' downstream effects require proteomic investigation.
Purpose of the Study:
- To identify proteins dysregulated at the proteomic level in AML.
- To investigate the role of specific mitochondrial proteins in AML progression.
- To explore novel therapeutic targets for AML.
Main Methods:
- Quantitative mass spectrometry performed in parallel with RNA sequencing.
- Utilized AML mouse models for integrated proteomic and transcriptomic analysis.
- Focused on silencing identified upregulated mitochondrial proteins (ETFA, ETFB).
Main Results:
- Identified 34 proteins upregulated in AML tumors, with unaltered transcriptional levels.
- Silencing of ETFA and ETFB increased mitochondrial activity and apoptosis in AML cells.
- ETFA and ETFB silencing showed minimal impact on normal human CD34+ cells.
Conclusions:
- ETFA and ETFB are potential therapeutic targets for AML.
- Protein expression changes, not reflected at the RNA level, are critical in AML.
- This study expands the understanding of AML molecular mechanisms and identifies new therapeutic strategies.
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