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Updated: Jul 8, 2025
Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
Somatic mutations of MLL4/COMPASS induce cytoplasmic localization providing molecular insight into cancer prognosis
Zibo Zhao1,2, Yuki Aoi1,2, Cassandra N Philips1,2
1Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
Abstract:
Cancer genome sequencing consortiums have recently catalogued an abundance of somatic mutations, across a wide range of human cancers, in the chromatin-modifying enzymes that regulate gene expression. Defining the molecular mechanisms underlying the potentially oncogenic functions of these epigenetic mutations could serve as the basis for precision medicine approaches to cancer therapy. MLL4 encoded by the KMT2D gene highly mutated in a large number of human cancers, is a key histone lysine monomethyltransferase within the Complex of Proteins Associated with Set1 (COMPASS) family that regulates gene expression through enhancer function, potentially functioning as a tumor suppressor. We report that the KMT2D mutations which cause MLL4 protein truncation also alter MLL4's subcellular localization, resulting in loss-of-function in the nucleus and gain-of-function in the cytoplasm. We demonstrate that isogenic correction of KMT2D truncation mutation rescues the aberrant localization phenotype and restores multiple regulatory functions of MLL4, including COMPASS integrity/stabilization, histone H3K4 mono-methylation, enhancer activation, and therefore transcriptional regulation. Moreover, isogenic correction diminishes the sensitivity of KMT2D-mutated cancer cells to targeted metabolic inhibition. Using immunohistochemistry, we identified that cytoplasmic MLL4 is unique to the tissue of bladder cancer patients with KMT2D truncation mutations. Using a preclinical carcinogen model of bladder cancer in mouse, we demonstrate that truncated cytoplasmic MLL4 predicts response to targeted metabolic inhibition therapy for bladder cancer and could be developed as a biomarker for KMT2D-mutated cancers. We also highlight the broader potential for prognosis, patient stratification and treatment decision-making based on KMT2D mutation status in MLL4 truncation-relevant diseases, including human cancers and Kabuki Syndrome.
Insights
Mutations in the KMT2D gene cause MLL4 protein to mislocalize, impairing its tumor-suppressing functions. Correcting this restores MLL4 activity and reduces cancer cell sensitivity to metabolic inhibitors, suggesting a new therapeutic strategy.
Area of Science:
- Epigenetics
- Cancer Genomics
- Molecular Biology
Background:
- Cancer genome sequencing reveals frequent mutations in chromatin-modifying enzymes.
- MLL4 (encoded by KMT2D) is a key regulator of gene expression via enhancers, potentially acting as a tumor suppressor.
- KMT2D mutations are prevalent in numerous human cancers.
Purpose of the Study:
- To investigate the functional consequences of KMT2D mutations on MLL4 protein.
- To explore the therapeutic potential of targeting KMT2D-mutated cancers.
- To identify MLL4 subcellular localization as a potential biomarker.
Main Methods:
- Analysis of KMT2D truncation mutations and MLL4 subcellular localization.
- Isogenic correction of KMT2D mutations in cancer cells.
- Assessment of MLL4's regulatory functions (COMPASS integrity, H3K4me1, enhancer activation).
- Evaluation of cancer cell sensitivity to metabolic inhibition.
- Immunohistochemistry on patient tissues and preclinical mouse models.
Main Results:
- KMT2D mutations cause MLL4 protein truncation, leading to nuclear loss-of-function and cytoplasmic gain-of-function.
- Isogenic correction restored MLL4's nuclear functions and reduced cancer cell sensitivity to metabolic inhibitors.
- Cytoplasmic MLL4 was specifically observed in bladder cancer patients with KMT2D truncation mutations.
- Truncated cytoplasmic MLL4 predicted response to targeted metabolic inhibition in a preclinical bladder cancer model.
Conclusions:
- KMT2D mutations disrupt MLL4 function and localization, offering a therapeutic vulnerability.
- Cytoplasmic MLL4 can serve as a predictive biomarker for metabolic inhibition therapy in KMT2D-mutated cancers.
- KMT2D mutation status has implications for prognosis, patient stratification, and treatment decisions in relevant diseases.
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