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4 recordsLinked to original sources
PubMed2025

MLL1 downregulation drives hair cell ferroptosis via mitochondrial and endoplasmic reticulum stress mechanisms through PERK-eIF2α-ATF4-Chop and PI3K/Akt-Lrp1 signaling pathway.

BACKGROUND: Sensorineural hearing loss is characterized by irreversible hair cell (HC) degeneration. Ferroptosis, which is marked by the accumulation of reactive oxygen species and elevated levels of lipid peroxidation products, has been shown to contribute to drug-mediated auditory impairment. This study aimed to elucidate the role of mixed-lineage leukemia 1 (MLL1) in HC survival in the auditory system. METHODS: The HEI-OC1 auditory cell line and postnatal cochlear explants were evaluated using MM-102, a specific MLL1 histone methyltransferase inhibitor. Western blotting, quantitative polymerase chain reaction, electron microscopy, and immunofluorescence were used to elucidate the role of MLL1 in regulating ferroptosis in HC injury. RNA sequencing (RNA-seq) was used to analyze the molecular mechanisms of MLL1 intervention in HC injury from an epigenetic perspective. RESULTS: Our findings demonstrated that immunofluorescence staining revealed a crucial role of MM-102 in promoting intracellular accumulation of lipid peroxides and ferrous ions. Subsequent analysis showed MLL1 downregulation-induced mitochondrial dysfunction and endoplasmic reticulum (ER) stress, with transmission electron microscopy imaging confirming ultrastructural alterations in mitochondria and ER. Mechanistic investigations identified the PERK-eIF2α-ATF4-Chop signaling axis as the regulatory pathway, evidenced by Western blotting quantification of phosphorylated PERK (p-PERK), ATF4, and Chop levels. RNA-seq analysis revealed 741 differentially expressed genes (335 upregulated and 406 downregulated). Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis specifically highlighted significant enrichment of the PI3K/Akt-Lrp1 pathway, with corresponding activation patterns of phospho (p)-Akt and Lrp1 confirmed through Western blotting analysis. CONCLUSIONS: MLL1 downregulation initiates ferroptosis in cochlear HCs. This process is intrinsically associated with the activation of mitochondrial dysfunction and ER stress. The study highlights the importance of MLL1 in HC survival, suggesting its potential as a therapeutic target for treating hearing loss.

Endoplasmic Reticulum Stress↗
PubMed2025

Functional Mapping of Epigenomic Regulators Uncovers Coordinated Tumor Suppression by the HBO1 and MLL1 Complexes.

UNLABELLED: Epigenomic dysregulation is widespread in cancer. However, the specific epigenomic regulators and the processes they control to drive cancer phenotypes are poorly understood. We used a novel high-throughput in vivo method to perform iterative functional screens of >250 epigenomic regulators within autochthonous oncogenic Kras-driven lung tumors. We identified many previously unappreciated epigenomic tumor suppressor and tumor dependency genes. We show that a specific HBO1 complex and MLL1 complex are robust tumor suppressors in lung adenocarcinoma. Histone modifications generated by the HBO1 complex are frequently reduced in human lung adenocarcinomas and are associated with worse clinical features. HBO1 and MLL1 complexes co-occupy shared genomic regions, affect chromatin accessibility, and control the expression of canonical tumor suppressor genes and lineage fidelity. The HBO1 complex is epistatic with the MLL1 complex and other tumor suppressor genes in lung adenocarcinoma development. Collectively, these results provide a phenotypic roadmap of epigenomic regulators in lung tumorigenesis in vivo. SIGNIFICANCE: Using a novel functional genomics method in vivo, we investigated epigenomic regulators in lung tumorigenesis. We discovered multiple novel genes that affect tumor growth. We show that the HBO1 and MLL1 complexes interact to suppress lung adenocarcinoma. Our findings provide broad insights into the epigenomic regulatory landscape of lung cancer.

Humans↗
PubMed2025

Therapeutic targeting of WDR5-MLL1 by EMBOW-derived peptides suppresses leukemia progression.

WD40 repeat-containing protein 5 (WDR5) is a core component of the SET1/mixed lineage leukemia (MLL) complex that regulates gene expression via H3K4 methylation and plays a key role in maintaining oncogenic gene expression programs, particularly in MLL1-rearranged leukemias. In this study, we leveraged a microprotein, endogenous microprotein binder of WDR5 (EMBOW), to develop peptide-based inhibitors that specifically targeted WDR5. Through comprehensive biophysical analyses and high-resolution structural studies, we revealed that EMBOW mainly bound to the WDR5 interaction (WIN) site of WDR5. Structure-guided optimization led to the development of EMBOW-derived peptides, notably Ac7, which exhibited high affinity for WDR5 (Kd = 9.17 ± 4.01 nM). These peptides effectively inhibited H3K4 methylation, suppressed oncogenic gene expression, and impeded leukemia cell proliferation in vitro. Importantly, in xenograft mouse models, Ac7 demonstrated significant anti-tumor activity with low toxicity. This work offers a promising strategy for targeting epigenetic regulators with peptide-based therapeutics, providing a foundation for innovative treatments in leukemia.

Humans↗
PubMed2024

Engineering an inducible leukemia-associated fusion protein enables large-scale ex vivo production of functional human phagocytes.

Ex vivo expansion of human CD34+ hematopoietic stem and progenitor cells remains a challenge due to rapid differentiation after detachment from the bone marrow niche. In this study, we assessed the capacity of an inducible fusion protein to enable sustained ex vivo proliferation of hematopoietic precursors and their capacity to differentiate into functional phagocytes. We fused the coding sequences of an FK506-Binding Protein 12 (FKBP12)-derived destabilization domain (DD) to the myeloid/lymphoid lineage leukemia/eleven nineteen leukemia (MLL-ENL) fusion gene to generate the fusion protein DD-MLL-ENL and retrovirally expressed the protein switch in human CD34+ progenitors. Using Shield1, a chemical inhibitor of DD fusion protein degradation, we established large-scale and long-term expansion of late monocytic precursors. Upon Shield1 removal, the cells lost self-renewal capacity and spontaneously differentiated, even after 2.5 y of continuous ex vivo expansion. In the absence of Shield1, stimulation with IFN-γ, LPS, and GM-CSF triggered terminal differentiation. Gene expression analysis of the obtained phagocytes revealed marked similarity with naïve monocytes. In functional assays, the novel phagocytes migrated toward CCL2, attached to VCAM-1 under shear stress, produced reactive oxygen species, and engulfed bacterial particles, cellular particles, and apoptotic cells. Finally, we demonstrated Fcγ receptor recognition and phagocytosis of opsonized lymphoma cells in an antibody-dependent manner. Overall, we have established an engineered protein that, as a single factor, is useful for large-scale ex vivo production of human phagocytes. Such adjustable proteins have the potential to be applied as molecular tools to produce functional immune cells for experimental cell-based approaches.

Humans↗