CLINICAL AND BIOLOGICAL SIGNIFICANCE OF MITOCHONDRIAL TRNA GUANYLYLTRANSFERASE
- 1Universidade de São Paulo, São Paulo, SP, Brazil
- 2University Medical Center Groningen, Netherlands
Abstract
Background: Given the enhanced mtDNA copy number and mitochondrial metabolism dependency in AML, we previously established the MITO-RS, a prognostic risk score based on mtDNA modulators, including THG1L, which is necessary for myeloid cell viability; however, its precise biological and clinical implications in AML remain to be fully elucidated. Aim: To investigate the clinical relevance and biological roles of THG1L in AML. Methods: Clinical and molecular characterization was conducted using three independent public datasets: TCGA, BeatAML, and the CPTAC multi-omic cohort. Bulk transcriptomic and proteomic analyses comprised WGCNA, Gene Ontology, GSEA, and CIBERSORTx. Additionally, scRNA-seq datasets from healthy and AML bone marrow (BM) were processed to evaluate DEGs and THG1L-associated MSigDB signatures via UCell scoring. Thresholds for significance were set at p < 0.05, FDR < 0.05, and |NES| > 1.5. Results: Across all public cohorts, increased THG1L expression was associated with higher overall survival at both the transcriptomic and proteomic levels. The THG1L-high group had a higher prevalence of non-monocytic and CEBPA-mutated AML, whereas the THG1L-low group had a higher prevalence of TP53 mutation. Transcriptomic and proteomic profiling revealed that THG1L overexpression upregulated mitochondrial energetic and biosynthetic metabolism, mRNA and tRNA processing, and global cellular translation. Furthermore, cellular deconvolution analysis showed an enrichment of quiescent leukemic stem cells and a reduction of monocytes in THG1L-high samples. THG1L-differentially expressed genes and scGSEA confirmed these biosynthetic and energetic signatures in both leukemic and healthy BM. Within single-cell analyses, THG1L-high cells exhibited enrichment in oxidative phosphorylation, ribosomal, and translation signatures. scRNA-seq also revealed decreased THG1L expression in AML compared to healthy BM, where THG1L expression was sparse, peaking in early erythroid cells, which remained the most enriched compartment for THG1L-high AML cells. Conclusion: These findings establish THG1L as a favorable prognostic marker in AML, with its overexpression closely linked to enhanced constitutive RNA metabolism, mRNA translation, and OXPHOS signatures, thereby highlighting its biological relevance in healthy and leukemic myeloid cells.
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BibTeX
@article{santos2026clinical,
title = {{CLINICAL AND BIOLOGICAL SIGNIFICANCE OF MITOCHONDRIAL TRNA GUANYLYLTRANSFERASE}},
author = {Isabelle Caroline SANTOS and Juan Luiz COELHO-SILVA and Diego Antonio PEREIRA-MARTINS and João Agostinho MACHADO-NETO},
journal = {Hematology, Transfusion and Cell Therapy},
year = {2026},
month = oct,
doi = {10.1016/j.htct.2026.107570},
url = {https://doi.org/10.1016/j.htct.2026.107570},
note = {CC BY},
}
RIS
TY - JOUR
TI - CLINICAL AND BIOLOGICAL SIGNIFICANCE OF MITOCHONDRIAL TRNA GUANYLYLTRANSFERASE
AU - Isabelle Caroline SANTOS
AU - Juan Luiz COELHO-SILVA
AU - Diego Antonio PEREIRA-MARTINS
AU - João Agostinho MACHADO-NETO
PY - 2026
DA - 2026/10/23
JO - Hematology, Transfusion and Cell Therapy
DO - 10.1016/j.htct.2026.107570
UR - https://doi.org/10.1016/j.htct.2026.107570
AB - Background: Given the enhanced mtDNA copy number and mitochondrial metabolism dependency in AML, we previously established the MITO-RS, a prognostic risk score based on mtDNA modulators, including THG1L, which is necessary for myeloid cell viability; however, its precise biological and clinical implications in AML remain to be fully elucidated. Aim: To investigate the clinical relevance and biological roles of THG1L in AML. Methods: Clinical and molecular characterization was conducted using three independent public datasets: TCGA, BeatAML, and the CPTAC multi-omic cohort. Bulk transcriptomic and proteomic analyses comprised WGCNA, Gene Ontology, GSEA, and CIBERSORTx. Additionally, scRNA-seq datasets from healthy and AML bone marrow (BM) were processed to evaluate DEGs and THG1L-associated MSigDB signatures via UCell scoring. Thresholds for significance were set at p < 0.05, FDR < 0.05, and |NES| > 1.5. Results: Across all public cohorts, increased THG1L expression was associated with higher overall survival at both the transcriptomic and proteomic levels. The THG1L-high group had a higher prevalence of non-monocytic and CEBPA-mutated AML, whereas the THG1L-low group had a higher prevalence of TP53 mutation. Transcriptomic and proteomic profiling revealed that THG1L overexpression upregulated mitochondrial energetic and biosynthetic metabolism, mRNA and tRNA processing, and global cellular translation. Furthermore, cellular deconvolution analysis showed an enrichment of quiescent leukemic stem cells and a reduction of monocytes in THG1L-high samples. THG1L-differentially expressed genes and scGSEA confirmed these biosynthetic and energetic signatures in both leukemic and healthy BM. Within single-cell analyses, THG1L-high cells exhibited enrichment in oxidative phosphorylation, ribosomal, and translation signatures. scRNA-seq also revealed decreased THG1L expression in AML compared to healthy BM, where THG1L expression was sparse, peaking in early erythroid cells, which remained the most enriched compartment for THG1L-high AML cells. Conclusion: These findings establish THG1L as a favorable prognostic marker in AML, with its overexpression closely linked to enhanced constitutive RNA metabolism, mRNA translation, and OXPHOS signatures, thereby highlighting its biological relevance in healthy and leukemic myeloid cells.
SN - 2531-1379
SN - 2531-1387
ER -