UTX condensation underlies its tumour-suppressive activity

Shi, Bi; Li, Wei; Song, Yansu; Wang, Zhenjia; Jü, Rui; Ulman, Aleksandra; Hu, Jing; Palomba, Francesco; Zhao, Ying; Le, John Philip; Jarrard, William; Dimoff, David; Digman, Michelle A.; Gratton, Enrico; Zang, Chongzhi; Jiang, Hao

doi:10.1038/s41586-021-03903-7

Cited by 140 publications

(154 citation statements)

References 61 publications

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“…23 ). These results demonstrate that an N-terminal truncation of UTX lacking the JmjC demethylase domain 86–89 and a recently reported intrinsically disordered region 90 is both necessary and sufficient to drive tumor suppressive responses in this context.…”

Section: Resultssupporting

confidence: 59%

“…Our study also shows that the first 500 amino acids of UTX (lacking the demethylase domain) are sufficient to induce full length UTX-dependent cellular and transcriptional phenotypes. This finding is particularly interesting given a recent study suggesting that UTX requires a much bigger protein fragment to drive tumor suppressive activity and transcriptional regulation via phase separation mechanisms 90 . Instead, our study decisively demonstrates that the first 500 amino acids of UTX (lacking the core intrinsically disordered region defined by Shi et al 90 ) are necessary and sufficient to drive tumor suppressive responses in the context of Menin-MLL inhibition.…”

Section: Discussionmentioning

confidence: 87%

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A molecular switch between mammalian MLL complexes dictates response to Menin-MLL inhibition

Soto‐Feliciano

Sánchez‐Rivera

Perner

et al. 2021

Preprint

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The chromatin adaptor Menin interacts with oncogenic fusion proteins encoded by MLL1- rearrangements (MLL1-r), and small molecules that disrupt these associations are currently in clinical trials for the treatment of leukemia. Here, we delineate a molecular switch between the MLL1-Menin and MLL3/4-UTX chromatin modifying complexes that dictates response to Menin-MLL inhibitors. We show that Menin safeguards leukemia cell fitness by impeding binding of the histone demethylase UTX at a subset of non-canonical target gene promoters. Disrupting the interaction between Menin and MLL1 leads to UTX-dependent transcriptional activation of genes with tumor suppressive function. We show that this epigenetic mechanism is operative in murine and human models of AML, and clinical responses to Menin-MLL inhibition in primary human leukemia are accompanied by induction of tumor suppressive gene expression at Menin-UTX targets. These findings shed light on the context-dependent and often antagonistic roles that chromatin regulators exhibit in development and disease and provide mechanistic insight for rational design of targeted epigenetic therapies.

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Section: Resultssupporting

confidence: 59%

Section: Discussionmentioning

confidence: 87%

A molecular switch between mammalian MLL complexes dictates response to Menin-MLL inhibition

Soto‐Feliciano

Sánchez‐Rivera

Perner

et al. 2021

Preprint

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“…Consequently, this mutant also has reduced tumor-suppressive activity. 4 These findings join our previous studies in showing that the biophysical properties of protein condensates are important for a gene regulator in controlling tumorigenesis. 7 , 8 …”

supporting

confidence: 85%

“…Our recent work shows that UTX undergoes liquid–liquid phase separation that is mediated by its core Intrinsically Disordered Region (cIDR), and this property is critical for its tumor suppressive activity in leukemia and pancreatic cancer models. 4 We show that the cIDR is lost in the most frequent UTX mutation in all cancers, and it is the loss of cIDR, not the region after IDR (including the catalytic region), that is responsible for UTX inactivation as a tumor suppressor in these patients. UTX’s tumor suppressive activity is abolished by mutagenesis in cIDR, but can be regained in chimeric proteins that substitute the cIDR with a condensation-capable IDR from irrelevant proteins.…”

mentioning

confidence: 76%

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Epigenetic condensates regulate chromatin activity and tumorigenesis

Shi

Jiang

2021

Molecular & Cellular Oncology

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KMT2D Deficiency Promotes Myeloid Leukemias which Is Vulnerable to Ribosome Biogenesis Inhibition

Zhong

Zhang

et al. 2023

Advanced Science

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KMT2C and KMT2D are the most frequently mutated epigenetic genes in human cancers. While KMT2C is identified as a tumor suppressor in acute myeloid leukemia (AML), the role of KMT2D remains unclear in this disease, though its loss promotes B cell lymphoma and various solid cancers. Here, it is reported that KMT2D is downregulated or mutated in AML and its deficiency, through shRNA knockdown or CRISPR/Cas9 editing, accelerates leukemogenesis in mice. Hematopoietic stem and progenitor cells and AML cells with Kmt2d loss have significantly enhanced ribosome biogenesis and consistently, enlarged nucleolus, increased rRNA and protein synthesis rates. Mechanistically, it is found that KMT2D deficiency leads to the activation of the mTOR pathway in both mouse and human AML cells. Kmt2d directly regulates the expression of Ddit4, a negative regulator of the mTOR pathway. Consistent with the abnormal ribosome biogenesis, it is shown that CX‐5461, an inhibitor of RNA polymerase I, significantly restrains the growth of AML with Kmt2d loss in vivo and extends the survival of leukemic mice. These studies validate KMT2D as a de facto tumor suppressor in AML and reveal an unprecedented vulnerability to ribosome biogenesis inhibition.

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UTX condensation underlies its tumour-suppressive activity

Cited by 140 publications

References 61 publications

A molecular switch between mammalian MLL complexes dictates response to Menin-MLL inhibition

A molecular switch between mammalian MLL complexes dictates response to Menin-MLL inhibition

Epigenetic condensates regulate chromatin activity and tumorigenesis

KMT2D Deficiency Promotes Myeloid Leukemias which Is Vulnerable to Ribosome Biogenesis Inhibition

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