ASH1L Links Histone H3 Lysine 36 Dimethylation to MLL Leukemia

Zhu, Li; Li, Qin; Wong, Stephen H.K.; Huang, Min; Klein, Brianna J.; Shen, Jinfeng; Ikenouye, Larissa; Onishi, Masayuki; Schneidawind, Dominik; Buechele, Corina; Hansen, Larry G.; Duque‐Afonso, Jesús; Zhu, Fangfang; Martín, Glòria Mas; Gozani, Or; Majeti, Ravindra; Kutateladze, Tatiana G.; Cleary, Michael L.

doi:10.1158/2159-8290.cd-16-0058

Cited by 127 publications

(141 citation statements)

References 51 publications

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Section: Ash1l: Hox Gene Activator With Emerging Role In Cancermentioning

confidence: 74%

“…ASH1L-deficient HSCs are also unable to reconstitute bone marrow output when transplanted into lethally irradiated mice [7]. These findings indicate that ASH1L maintains quiescence and self-renewal potential of long-term HSCs, providing a foundation for a recent study suggesting that ASH1L may also regulate the stemness properties of leukemic stem cells [78].ASH1L has been linked to liver fibrosis, facioscapulohumeral muscular dystrophy and cancer through its role in gene activation [79,80]. ASH1L activates HOXA genes and MEIS1 in mouse HSCs [7] and activates HOXB and HOXC genes in human erythroleukemic K562 cells [81].…”

mentioning

confidence: 74%

“…For example, overexpression of HOXA9 is highly associated with a poor prognosis in AML [83], and HOXA9 and its collaborator MEIS1 are required for survival of MLLrearranged leukemia cells [84,85]. Indeed, a recent study showed that ASH1L is required for HOXA9 and MEIS1 expression in MLL-rearranged leukemia, and future science group H3K36 methyltransferases as cancer drug targets: rationale & perspectives for inhibitor development Review knockdown of ASH1L induces differentiation and prolongs survival in a mouse model of the disease [78]. The authors propose that H3K36 dimethylation catalyzed by ASH1L is bound by the H3K36me2 reader protein LEDGF, which recruits MLL to maintain target gene expression [78].…”

Section: Ash1l: Hox Gene Activator With Emerging Role In Cancermentioning

confidence: 99%

“…Indeed, a recent study showed that ASH1L is required for HOXA9 and MEIS1 expression in MLL-rearranged leukemia, and future science group H3K36 methyltransferases as cancer drug targets: rationale & perspectives for inhibitor development Review knockdown of ASH1L induces differentiation and prolongs survival in a mouse model of the disease [78]. The authors propose that H3K36 dimethylation catalyzed by ASH1L is bound by the H3K36me2 reader protein LEDGF, which recruits MLL to maintain target gene expression [78]. Additional evidence that ASH1L KMTase activity is important for its gene activating function comes from a mouse model with a targeted in-frame deletion of the ASH1L SET domain [86].…”

Section: Ash1l: Hox Gene Activator With Emerging Role In Cancermentioning

confidence: 99%

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H3K36 Methyltransferases as Cancer Drug Targets: Rationale and Perspectives for Inhibitor Development

2016

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Methylation at histone 3, lysine 36 (H3K36) is a conserved epigenetic mark regulating gene transcription, alternative splicing and DNA repair. Genes encoding H3K36 methyltransferases (KMTases) are commonly overexpressed, mutated or involved in chromosomal translocations in cancer. Molecular biology studies have demonstrated that H3K36 KMTases regulate oncogenic transcriptional programs. Structural studies of the catalytic SET domain of H3K36 KMTases have revealed intriguing opportunities for design of small molecule inhibitors. Nevertheless, potent inhibitors for most H3K36 KMTases have not yet been developed, underlining the challenges associated with this target class. As we now have strong evidence linking H3K36 KMTases to cancer, drug development efforts are predicted to yield novel compounds in the near future. Cellular development and differentiation are controlled by post-translational modifications on DNA and histone proteins, forming an epigenetic (above the genes) regulatory network. Disruption of epigenetic pathways is a nearly universal feature of cancer, causing aberrations in gene expression and genome integrity (reviewed in [1]). A key group of epigenetic enzymes disrupted in cancer is the lysine methyltransferases (KMTases), which install methyl groups on histone proteins. In cancer cells, methylation performed by KMTases drives proliferation and halts differentiation by modifying gene transcription and other DNA-templated processes [2][3][4]. Over the past decade, KMTases have emerged as important drug targets for both industrial and academic research groups. Some progress has been made, most notably by selective inhibitors for the EZH2 and DOT1L KMTases that have reached clinical trials for the treatment of nonHodgkin lymphoma and acute leukemia, respectively [5,6]. Nevertheless, selective and cell permeable inhibitors for many KMTases remain unavailable.Methylation at H3K36 represents a particularly important chromatin mark implicated in diverse forms of cancer. KMTases with specificity toward H3K36 are overexpressed in cancer cells and have been characterized as regulators of cell growth, differentiation, stemness and DNA repair pathways [7][8][9]. However, very few selective and cell-active small molecule inhibitors of H3K36-specfic KMTases have been reported to date. In this article, we provide an overview of cellular pathways involving H3K36 methylation and discuss the diverse functions carried out by the eight different human H3K36-specific KMTases. Then we analyze structural characteristics of the catalytic SET domain of H3K36 KMTases and evaluate prospects for their inhibition by small molecules. Review Rogawski, Grembecka & Cierpicki We conclude with a discussion of the challenges and o pportunities for targeting these proteins. SPECIAL FOCUS y Epigenetic drug discovery H3K36 methylation regulates diverse processes implicated in cancerH3K36 methylation participates in a wide variety of nuclear pathways. Many of these processes, including transcriptional regulation, alternative spli...

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Section: Ash1l: Hox Gene Activator With Emerging Role In Cancermentioning

confidence: 74%

mentioning

confidence: 74%

Section: Ash1l: Hox Gene Activator With Emerging Role In Cancermentioning

confidence: 99%

Section: Ash1l: Hox Gene Activator With Emerging Role In Cancermentioning

confidence: 99%

See 2 more Smart Citations

H3K36 Methyltransferases as Cancer Drug Targets: Rationale and Perspectives for Inhibitor Development

2016

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“…In this issue of Cancer Discovery , Zhu and colleagues uncover another epigenetic Achilles' heel of MLL-rearranged leukemia ( 6 ). In normal hematopoiesis, MLL cooperates with another epigenetic writer, the H3K36 methyltransferase ASH1L, to maintain self-renewal in quiescent HSCs ( 7 ).…”

mentioning

confidence: 99%

An Achilles' Heel for MLL-Rearranged Leukemias: Writers and Readers of H3 Lysine 36 Dimethylation

Balbach

Orkin

2016

Cancer Discovery

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Summary: Histone H3 lysine 36 dimethylation (H3K36me2), a modifi cation associated with transcriptional activation, is required for mixed-lineage leukemia -dependent transcription and leukemic transformation. In this issue of Cancer Discovery , Zhu and colleagues map the network of readers, writers, and erasers of H3K36me2 and uncover the ASH1L histone methyltransferase as a novel target for therapeutic intervention. Cancer Discov; 6(7); 700-2.

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SMYD2 Drives Mesendodermal Differentiation of Human Embryonic Stem Cells Through Mediating the Transcriptional Activation of Key Mesendodermal Genes

Bai

Zhang

et al. 2019

Stem Cells

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Histone methyltransferases play a critical role in early human development, whereas their roles and precise mechanisms are less understood. SET and MYND domain-containing protein 2 (SMYD2) is a histone lysine methyltransferase induced during early differentiation of human embryonic stem cells (hESCs), but little is known about its function in undifferentiated hESCs and in their early lineage fate decision as well as underlying mechanisms. Here, we explored the role of SMYD2 in the self-renewal and mesendodermal lineage commitment of hESCs. We demonstrated that the expression of SMYD2 was significantly enhanced during mesendodermal but not neuroectodermal differentiation of hESCs. SMYD2 knockout (SMYD2−/−) did not affect self-renewal and early neuroectodermal differentiation of hESCs, whereas it blocked the mesendodermal lineage commitment. This phenotype was rescued by reintroduction of SMYD2 into the SMYD2−/− hESCs. Mechanistically, the bindings of SMYD2 at the promoter regions of critical mesendodermal transcription factor genes, namely, brachyury (T), eomesodermin (EOMES), mix paired-like homeobox (MIXL1), and goosecoid homeobox (GSC) were significantly enhanced during mesendodermal differentiation of SMYD2+/+ hESCs but totally suppressed in SMYD2−/− ones. Concomitantly, such a suppression was associated with the remarkable reduction of methylation at histone 3 lysine 4 and lysine 36 but not at histone 4 lysine 20 globally and specifically on the promoter regions of mesendodermal genes, namely, T, EOMES, MIXL1, and GSC. These results reveal that the histone methyltransferase SMYD2 is dispensable in the undifferentiated hESCs and the early neuroectodermal differentiation, but it promotes the mesendodermal differentiation of hESCs through the epigenetic control of critical genes to mesendodermal lineage commitment. Stem Cells 2019;37:1401–1415

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ASH1L Links Histone H3 Lysine 36 Dimethylation to MLL Leukemia

Cited by 127 publications

References 51 publications

H3K36 Methyltransferases as Cancer Drug Targets: Rationale and Perspectives for Inhibitor Development

H3K36 Methyltransferases as Cancer Drug Targets: Rationale and Perspectives for Inhibitor Development

An Achilles' Heel for MLL-Rearranged Leukemias: Writers and Readers of H3 Lysine 36 Dimethylation

SMYD2 Drives Mesendodermal Differentiation of Human Embryonic Stem Cells Through Mediating the Transcriptional Activation of Key Mesendodermal Genes

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