Signatures of polycomb repression and reduced H3K4 trimethylation are associated with p15INK4b DNA methylation in AML

Paul, Thomas A.; Bies, Juraj; Small, Donald; Wolff, Linda

doi:10.1182/blood-2009-07-233858

Cited by 78 publications

(81 citation statements)

References 47 publications

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“…Moreover, mutation of Ezh2 Y641 has been described in lymphomas 7 and results in Ezh2 gain-of-function 8,9 . Oncogenic activity of Ezh2 has also been described in myelodysplastic syndromes 10 and in acute myeloid leukaemia 11 , where it has been identified as a potential drug target 12 . However, acquired Ezh2 mutations in myeloid neoplasms have also been found, indicating that Ezh2 may act as a tumour suppressor 13,14 .…”

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confidence: 99%

Ectopic expression of the histone methyltransferase Ezh2 in haematopoietic stem cells causes myeloproliferative disease

et al. 2012

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Recent evidence shows increased and decreased expression of Ezh2 in cancer, suggesting a dual role as an oncogene or tumour suppressor. To investigate the mechanism by which Ezh2-mediated H3K27 methylation leads to cancer, we generated conditional Ezh2 knock-in (Ezh2-KI) mice. Here we show that induced Ezh2 haematopoietic expression increases the number and proliferation of repopulating haematopoietic stem cells. Ezh2-KI mice develop myeloproliferative disorder, featuring excessive myeloid expansion in bone marrow and spleen, leukocytosis and splenomegaly. Competitive and serial transplantations demonstrate progressive myeloid commitment of Ezh2-KI haematopoietic stem cells. Transplanted self-renewing haematopoietic stem cells from Ezh2-KI mice induce myeloproliferative disorder, suggesting that the Ezh2 gainof-function arises in the haematopoietic stem cell pool, and not at later stages of myelopoiesis. At the molecular level, Ezh2 regulates haematopoietic stem cell-specific genes such as Evi-1 and ntrk3, aberrantly found in haematologic malignancies. These results demonstrate a stem cell-specific Ezh2 oncogenic role in myeloid disorders, and suggest possible therapeutic applications in Ezh2-related haematological malignancies. Most low GC Gram-positive bacteria possess an essential walKR two-component system (TCS) for signal transduction involved in regulating cell wall homoeostasis. Despite the well-established intracellular regulatory mechanism, the role of this TCS in extracellular signal recognition and factors that modulate the activity of this TCS remain largely unknown. Here we identify the extracellular receptor of the kinase 'WalK' (erWalK) as a key hub for bridging extracellular signal input and intracellular kinase activity modulation in Staphylococcus aureus. Characterization of the crystal structure of erWalK revealed a canonical Per-Arnt-Sim (PAS) domain for signal sensing. Single amino-acid mutation of potential signal-transduction residues resulted in severely impaired function of WalKR. A small molecule derived from structure-based virtual screening against erWalK is capable of selectively activating the walKR TCS. The molecular level characterization of erWalK will not only facilitate exploration of natural signal(s) but also provide a template for rational design of erWalK inhibitors.

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confidence: 99%

Ectopic expression of the histone methyltransferase Ezh2 in haematopoietic stem cells causes myeloproliferative disease

et al. 2012

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“…Interestingly, entinostat also had an effect upon trimethylation of H3K4. Other HDAC inhibitors like PB, VPA (Nightingale et al, 2007) and trichostatin A (Paul et al, 2010) have been described to induce trimethylation of H3K4, suggesting a functional link between histone acetylation and histone methylation. The group of Constanze Bonifer described the interaction between AML1 (RUNX1) and the initiation of chromatin remodeling through trimethylation of H3K4 in pluripotent hematopoietic precursors cells, suggesting that Epigenetic regulation of LAT2 by AML1/ETO J Duque-Afonso et al the epigenetic changes of AML1/ETO target promoters may be due to modification not only in histone acetylation but also in histone methylation (Hoogenkamp et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

The HDAC class I-specific inhibitor entinostat (MS-275) effectively relieves epigenetic silencing of the LAT2 gene mediated by AML1/ETO

et al. 2011

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The chromosomal translocation (8;21) fuses the hematopoietic transcription factor AML1 (RUNX1) with ETO (RUNX1T1, MTG8), resulting in the leukemia-specific chimeric protein AML1/ETO. This fusion protein has been implicated in epigenetic silencing, recruiting histone deacetylases (HDACs) and DNA methyltransferases to target promoters. Previously, we have identified a novel in vivo AML1/ETO target gene, LAT2 (NTAL/LAB/ WBSCR5), which is involved in FceR I, c-Kit, B-cell and T-cell receptor signalling. We have now addressed the molecular mechanisms of AML1/ETO-mediated LAT2 repression. In Kasumi-1 cells, where AML1/ETO bound to the LAT2 gene, small interfering RNA (siRNA)-mediated AML1/ETO depletion caused upregulation of LAT2, suggesting a possible direct mechanism of repression. Expression of AML1/ETO was associated with a decrease in acetylation of histones H3, H3K9 and H4, and an increase in H3K9 and H3K27 trimethylation. The class I-specific HDAC inhibitors entinostat (MS-275) and mocetinostat (MGCD0103) induced LAT2 expression specifically in AML1/ETO-expressing cells, resulting in induction of several activating histone marks on the LAT2 gene, including trimethylation of histone H3K4. The combination of entinostat and decitabine increased acetylation of histones H3 and H4, as well as LAT2 mRNA expression, in an at least additive fashion. In conclusion, several repressive histone modifications mark the LAT2 gene in the presence of AML1/ETO, and LAT2 gene derepression is achieved by pharmacological inhibition of HDACs.

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“…Similar to DNA methylation, histone modifications are fully biochemically reversible, result in changes in the protein structure and affect the affinity of histone tails to DNA molecules (Varier & Timmers, 2011). Paul et al (2010) found that in AML cell lines with aberrant p15INK4b DNA hypermethylation, the histone 3 trimethylated at lysine 4 (H3K4me3), which is a transcriptional activation mark, was at lower levels than in AML cell lines without hypermethylation. Interestingly, irrespective of the methylation status of p15INK4b, this study also reported the presence of the repressive mark H3K27me3 (histone 3 trimethylated at lysine 27) at the 9p21 locus.…”

Section: Targeting P15ink4b For Re-expression In Aml and Mdsmentioning

confidence: 99%

p15INK4b, a Tumor Suppressor in Acute Myeloid Leukemia

Fares¹,

Wolff²,

Bies³

2011

Myeloid Leukemia - Basic Mechanisms of Leukemogenesis

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Signatures of polycomb repression and reduced H3K4 trimethylation are associated with p15INK4b DNA methylation in AML

Cited by 78 publications

References 47 publications

Ectopic expression of the histone methyltransferase Ezh2 in haematopoietic stem cells causes myeloproliferative disease

Ectopic expression of the histone methyltransferase Ezh2 in haematopoietic stem cells causes myeloproliferative disease

The HDAC class I-specific inhibitor entinostat (MS-275) effectively relieves epigenetic silencing of the LAT2 gene mediated by AML1/ETO

p15INK4b, a Tumor Suppressor in Acute Myeloid Leukemia

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