Friday, May 9, 2025
5/9/2025
Targeting mitochondrial RNA methylation in high-risk acute myeloid leukemia - Project Summary Acute myeloid leukemia (AML) is one of the most aggressive types of hematopoietic malignancy. Despite treatment advancements, over 70% of AML patients remain incurable. Individuals with MLL rearrangements (MLL- r, 5-10% of AML) and/or FLT3 internal tandem duplications (FLT3ITD, 20-25% of AML) experience a worse prognosis than others. Leukemia stem/initiating cells (LSCs/LICs) are recognized as the root cause of AML initiation, progression, and relapse, and these cells heavily depend on mitochondrial oxidative phosphorylation (OxPhos) for energy production. Thus, targeting mitochondrial metabolism emerges as an attractive strategy to eliminate LSCs/LICs for a potential cure. Intriguingly, the mitochondrion possesses its own circular genome, producing mitochondrial RNAs (mt-RNAs) which are decorated with various RNA modifications. Recent studies, including our own, suggest that RNA modifications are critical for post-transcriptional gene regulation during leukemogenesis, and targeting RNA modifications is a promising strategy to eradicate LSCs/LICs. However, the biological and pathological roles of mt-RNA modifications in AML are still unclear. Additionally, it remains unknown whether, and if so, how mt-RNA modifications coordinate mitochondrial-nuclear crosstalk for efficient energy conversion. To bridge these knowledge gaps, we conducted large-scale data analysis and identified mitochondrial methyltransferase like 17 (METTL17) as a novel vulnerability in AML. METTL17 knockout (KO) decreases cytosine methylation in mt-12S ribosomal (r)RNA, resulting in 12S rRNA decay and mitochondrial translation inhibition. This, in turn, suppresses AML growth, reduces OxPhos, and eliminates LSCs/LICs in MLL- r and FLT3ITD AML. METTL17 KO-mediated OxPhos reduction further decreases acetyl-CoA and nuclear histone H3 lysine 27 acetylation (H3K27ac), influencing nuclear gene expression, such as cyclin D3 (CCND3). Pharmacological inhibition of METTL17 using an in-house inhibitor shows robust anti-AML efficacy. Therefore, we hypothesize that METTL17, as a mitochondrial RNA methyltransferase, regulates OxPhos and sustains LSC/LIC frequency, making it a potential `druggable' target for AML. We propose three Specific Aims to test our hypothesis. Aim 1 will determine the functional importance of METTL17 in AML pathogenesis using mouse models. Aim 2 will dissect the molecular mechanisms through which METTL17 promotes leukemogenesis. Aim 3 will evaluate the therapeutic impact of pharmacologically inhibiting METTL17 in AML. This study is innovative and significant because it (i) advances our understanding of the pathological role of mt-RNA modification, (ii) introduces a novel concept that mt-RNA methylation regulates retrograde mitochondrial-nuclear communication via H3K27ac, and (iii) develops a specific and potent METTL17 inhibitor to improve outcomes of high-risk AML.
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