Multi-omics reveals mitochondrial metabolism proteins susceptible for drug discovery in AML

Mika Caplan,Karli J Wittorf,R Katherine Hyde,Catalina Amador,Samantha A Swenson,Tyler J Gilbreath,Kasidy K Weber,R Willow Hynes-Smith,Shannon M Buckley

doi:10.1038/s41375-022-01518-z

Mika Caplan, Karli J Wittorf + Show 7 more

Open Access

https://doi.org/10.1038/s41375-022-01518-z

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Journal: Leukemia	Publication Date: Feb 17, 2022
Citations: 8	License type: open-access

Affiliation: University of Nebraska Medical Center

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.

Highlights

Acute myeloid leukemia (AML) affects the hematopoietic system through abnormal proliferation of myeloid cells in the bone marrow (BM) and suppresses the production of healthy blood cells
We found that silencing of ETFA and ETFB in AML cell lines led to increased oxygen consumption rate (OCR), respiration, extracellular acidification rate (ECAR), ATP production, and spare respiratory capacity (Fig. 5D–G; Supplementary Fig. 4B–G)
It is believed that leukemic stem cells (LSCs) rely heavily on oxidative phosphorylation (OXPHOS) and metabolic mechanisms of the mitochondria in order to maintain self-renewal and survival [48,49,50]

Summary

Introduction

Acute myeloid leukemia (AML) affects the hematopoietic system through abnormal proliferation of myeloid cells in the bone marrow (BM) and suppresses the production of healthy blood cells. AML is the leading cause of death among adult leukemia patients, it represents only 35% of those diagnosed [1]. Two genomic alterations found in patients are Mixed Lineage Leukemia (MLL) rearrangements and an inversion of chromosome 16 (Inv(16)) [3,4,5,6]. The protein histone-lysine N-methyltransferase 2A (KMT2A), known as the mixed-lineage leukemia 1 (MLL1) gene, contains domains essential for transcriptional activity and chromatin modifications during early hematopoiesis, and fusion proteins generated from each translocation lead to aberrant transcription of MLL target genes [7,8,9,10,11]. AML::MLL rearrangements account for 10% of all diagnosed leukemias and these subtypes typically tend to have worse patient prognoses [12,13,14]

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