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PubMed2026

AML1-ETO hijacks a distal enhancer of NAT10 to reprogram glutathione metabolism and sustain leukemia stem cell stemness.

Chromosomal translocations produce oncogenic fusion proteins such as AML1-ETO, which predominantly occupy gene promoters to induce transcriptional reprogramming in leukemia stem cells (LSCs), consequently driving the pathogenesis of t(8;21) acute myeloid leukemia (AML). However, whether AML1-ETO is recruited to additional regulatory DNA elements to orchestrate oncogenic gene expression programs has not been fully addressed. Here, we define AML1-ETO and H3K27ac CUT&Tag landscapes in primary t(8;21) AML CD34+ cells and t(8;21) AML cell lines, revealing AML1-ETO binding at a distal enhancer of the RNA N4-acetylcytidine (ac4C) writer N-acetyltransferase 10 (NAT10), thereby driving its transcriptional activation. Genetic ablation or pharmacological inhibition of NAT10 restricted the survival and self-renewal of LSCs in primary t(8;21) AML CD34+ cells, as well as in a retroviral AML1-ETO9a-driven t(8;21) AML mouse model, establishing NAT10 as a potential therapeutic vulnerability. Mechanistically, NAT10 is recruited to glutathione S-transferase omega 2 (GSTO2) mRNA to catalyze ac4C modification, thereby enhancing transcript stability and reprogramming glutathione metabolism, as demonstrated by ac4C profiling, RNA immunoprecipitation (RIP), and dCas13b-NAT10-based analyses. Silencing of GSTO2 in primary t(8;21) AML CD34+ cells decreased intracellular reduced glutathione (GSH) levels and compromised LSC survival and self-renewal, whereas GSTO2 overexpression or GSH supplementation largely rescued LSC maintenance following NAT10 loss. Collectively, these findings enrich and extend the understanding of AML1-ETO regulatory programs by linking distal enhancer activity to a NAT10-GSTO2 ac4C-GSH axis that integrates epigenomic, posttranscriptional, and metabolic reprogramming to sustain LSC stemness, highlighting this circuit as a potential therapeutic vulnerability in t(8;21) AML.

Humans↗

PubMed2026

Measurable Residual Disease and the Unresolved Biology of Leukemic Stem Cells.

Measurable residual disease (MRD) testing has transformed the management of hematologic cancers by enabling detection of residual malignant cells after therapy. Current approaches rely on qPCR and next-generation sequencing to monitor leukemia-associated somatic mutations, while multiparameter flow cytometry identifies aberrant leukemic immunophenotypes. Although these methods provide valuable prognostic and therapeutic information, MRD negativity remains an imperfect surrogate for cure. Most MRD platforms evaluate CD45+, rapidly dividing leukemic populations and fail to detect quiescent cells that may survive cytotoxic therapies which efficiently target proliferating hematopoietic cells. Relapse frequently occurs despite deep molecular remission, suggesting persistence of rare leukemic stem cells (LSCs) that are intrinsically resistant to chemotherapy and targeted therapies. The paradox of relapse despite molecular remission could be explained by the presence of very small embryonic-like stem cells (VSELs) which are pluripotent, quiescent stem cells sitting at the top of cellular hierarchy in multiple adult tissues including bone marrow. A pluripotent VSEL divides through asymmetrical cell division to give rise to two cells of different sizes and fates, smaller cell is to self-renew while the bigger is lineage-restricted and tissue-committed progenitor which undergoes extensive epigenetic changes, divides rapidly and undergoes clonal expansion before further differentiation. Dysfunctions of VSELs initiate both solid and hematologic cancers. Based on this view, somatic mutations monitored during MRD assessment possibly represent downstream consequences of clonal expansion rather than the initiating drivers of disease persistence. Thus, exclusive monitoring of somatic mutations and CD45 + leukemic populations possibly overlook rare, small-sized, CD45- VSELs that contribute to therapeutic resistance and relapse.

Humans↗

PubMed2025

Guanine nucleotide biosynthesis blockade impairs MLL complex formation and sensitizes leukemias to menin inhibition.

Targeting the dependency of MLL-rearranged (MLLr) leukemias on menin with small molecule inhibitors has opened new therapeutic strategies for these poor-prognosis diseases. However, the rapid development of menin inhibitor resistance calls for combinatory strategies to improve responses and prevent resistance. Here we show that leukemia stem cells (LSCs) of MLLr acute myeloid leukemia (AML) exhibit enhanced guanine nucleotide biosynthesis, the inhibition of which leads to myeloid differentiation and sensitization to menin inhibitors. Mechanistically, targeting inosine monophosphate dehydrogenase 2 (IMPDH2) reduces guanine nucleotides and rRNA transcription, leading to reduced protein expression of LEDGF and menin. Consequently, the formation and chromatin binding of the MLL-fusion complex is impaired, reducing the expression of MLL target genes. Inhibition of guanine nucleotide biosynthesis or rRNA transcription further suppresses MLLr AML when combined with a menin inhibitor. Our findings underscore the requirement of guanine nucleotide biosynthesis in maintaining the function of the LEDGF/menin/MLL-fusion complex and provide a rationale to target guanine nucleotide biosynthesis to sensitize MLLr leukemias to menin inhibitors.

Proto-Oncogene Proteins↗

PubMed2026

Comparative genomics and phylogenetic analysis of three Malvaceae species on the basis of chloroplast genomes.

INTRODUCTION: The Malvaceae family shows rich species diversity and has substantial economic and medicinal value. However, the frequent interspecific hybridization among members of this family has resulted in confused phylogenetic relationships among the groups, limiting the usefulness of traditional classification methods. METHODS: This study aimed to investigate the phylogenetic relationships among selected taxa of Malvaceae by evaluating 23 chloroplast (CP) genomes, including three newly assembled CP genomes. Among these three genomes, the CP genome of Hibiscus schizopetalus L. was reported for the first time, while the CP genomes of Alcea rosea L. and Hibiscus grewiifolius L., which have been deposited in NCBI, were re-analyzed here alongside newly generated data for comparative purposes. In addition, 20 downloaded CP genomes encompassing 13 genera were analyzed using SNPs in whole CP genomes data. RESULTS: The results showed that the genomes ranged from 160,403 to 161,978 base pairs in length and consisted of small single copies (SSCs) and large single copies (LSCs) separated by two inverted repeat sequences (IRs), forming a typical quadripartite circular structure. The entire genome sequence showed relative conservation across species in terms of structure, GC content, codon usage, and gene composition. The mutation sites were mainly located in the LSC and SSC regions, and the variability in the non-coding regions was higher than that in the coding regions. The nucleotide polymorphism (Pi) analysis identified the non-coding regions such as ndhF-rpl32 and psbZ-trnG as high variable hotspots. A maximum likelihood phylogenetic tree was constructed based on SNPs in whole CP genomes data. The phylogenetic analysis divided these 23 species into five highly supported clades. It also revealed a close sister-group relationship between Abelmoschus and Hibiscus species, suggesting that Hibiscus may have a separate lineage from okra species. DISCUSSION: In conclusion, the increasing availability of CP genome resources will enhance our understanding of the classification and evolutionary patterns of the Malvaceae family. The development of molecular markers will provide important molecular evidence for precise identification and classification revision of plants in this family.

Malvaceae↗