Ash1l controls quiescence and self-renewal potential in hematopoietic stem cells

Jones, Matthew M.; Chase, Jennifer; Brinkmeier, Michelle L.; Xu, Jing; Weinberg, Daniel N.; Schira, Julien; Friedman, Ann; Malek, Sami N.; Grembecka, Jolanta; Cierpicki, Tomasz; Dou, Yali; Camper, Sally A.; Maillard, Ivan

doi:10.1172/jci78124

Cited by 57 publications

(70 citation statements)

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“…ASH1L activates HOXA genes and MEIS1 in mouse HSCs [7] and activates HOXB and HOXC genes in human erythroleukemic K562 cells [81]. These findings are highly relevant because HOX genes are oncogenic drivers in many different blood and solid tumors [82].…”

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

confidence: 99%

“…ASH1L is homologous to Drosophila Ash1, a trithorax group protein that activates genes involved in development and differentiation [77]. In mammals, ASH1L deficiency causes a major reduction in longterm hematopoietic stem cells (HSCs) in bone marrow, but surprisingly has very modest effects on peripheral blood counts due to increased proliferation of progenitors downstream of HSCs [7]. ASH1L-deficient HSCs are also unable to reconstitute bone marrow output when transplanted into lethally irradiated mice [7].…”

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

confidence: 99%

“…Of these KMTases, the NSD proteins are perhaps the best characterized oncoproteins, as they play important roles in multiple cancer types and are found in fusion proteins due to chromosomal translocations in acute myeloid leukemia (AML) and multiple myeloma (MM) [3,8]. The ASH1L KMTase is also overexpressed in cancer and regulates stem cell potential [7]. SMYD2 has oncogenic activity in multiple cancers [40][41][42][43][44], but whether this function depends on KMTase activity toward H3K36 or another of its many substrates is uncertain.…”

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confidence: 99%

“…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.…”

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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: 99%

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

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

2016

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“…During fetal life, subsets of hematopoietic progenitors acquire long-term self-renewal potential as assessed after transplantation into lethally irradiated hosts, a functional property that has been used historically to define hematopoietic stem cells (HSCs) (1)(2)(3)(4). Fetal HSCs are thought to seed the more quiescent adult HSC compartment that will sustain the adult hematopoietic system, a process taking place in the bone marrow after it becomes available to support hematopoiesis (5)(6)(7). In parallel, fetal hematopoiesis generates subsets of macrophages and lymphocytes that are uniquely produced during fetal life, suggesting that they play a role in shaping the developing immune system's reactivity.…”

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Fetal hematopoietic stem cells are making waves

Waas

Maillard²

2017

Stem Cell Investig.

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Phenotypic and Functional Evaluation of Hematopoietic Stem and Progenitor Cells in Toxicology of Heavy Metals

Yang

Zhao

et al. 2018

CP Toxicology

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All blood cells are differentiated from hematopoietic stem and progenitor cells (HSPCs), a process known as hematopoiesis that can be influenced by a variety of environmental factors. In this unit, we introduce a couple of protocols including phenotypic analysis, mixed bone marrow (BM) chimera and rescue assays, colony-forming unit (CFU), and in vitro OP9 stromal cell differentiation assays for evaluating HSPCs in the BM of mice, and provide some examples of their implications in mouse models treated with heavy metals. The protocols for evaluating hematopoietic stem cells (HSCs) comprise phenotypic analysis and functional transplantation assays. The protocols for assessing hematopoietic progenitor cells (HPCs) consist of phenotypic analysis and in vitro differentiation assays. The main techniques applied in these protocols include flow cytometry (phenotypic analysis and sorting), irradiation, transplantation, and cell culture. © 2018 by John Wiley & Sons, Inc.

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Ash1l controls quiescence and self-renewal potential in hematopoietic stem cells

Cited by 57 publications

References 68 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

Fetal hematopoietic stem cells are making waves

Phenotypic and Functional Evaluation of Hematopoietic Stem and Progenitor Cells in Toxicology of Heavy Metals

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