A key role for <i>EZH2</i> and associated genes in mouse and human adult T-cell acute leukemia

Simon, Camille; Chagraoui, Jalila; Krošl, Jana; Gendron, Patrick; Wilhelm, Brian T.; Lemieux, Sébastien; Boucher, Geneviève; Chagnon, Pierre; Drouin, Simon; Lambert, Raphaëlle; Rondeau, Claude; Bilodeau, A.S.; Lavallée, Sylvie; Sauvageau, Martin; Hébert, Josée; Sauvageau, Guy

doi:10.1101/gad.186411.111

Cited by 248 publications

(238 citation statements)

References 28 publications

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“…26 EZH2, located on 7q36.1, has been shown to be mutated in myeloid malignancies and portends high-risk disease. [27][28][29] MLL5, located on 7q22.1, has been known to play a role in cell differentiation and self-renewal. [30][31][32] In our cohort, all cases had at least one commonly deleted region deleted.…”

Section: Discussionmentioning

confidence: 99%

“…Seven patients (cases 25,26,29,30,[32][33][34] had no indication for myeloid neoplasms and no follow-up bone marrow evaluation was done; eight patients (cases 20, 21, 24, 27, 28, 31, 35, 36) had undetectable del(7q) in the follow-up bone marrow and no indication for a secondary myeloid neoplasm; patient 19 was suspected to have a therapy-related myelodysplastic syndrome and died 4 months later but no follow-up bone marrow was performed; patient 39 had del(7q) detected intermittently in 5-10% metaphases, and no indication for a myeloid neoplasm. By the end of follow-up, 6 patients died of their primary cancer or complications, 13 were alive with no evidence of primary cancer or therapy-related myeloid neoplasms, 1 was alive with primary cancer and 1 was lost to follow-up (Table 1).…”

Section: Follow-up and Outcomesmentioning

confidence: 99%

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Newly emerged isolated Del(7q) in patients with prior cytotoxic therapies may not always be associated with therapy-related myeloid neoplasms

et al. 2016

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Deletion 7q is a common chromosomal abnormality in myeloid neoplasms. Detection of del(7q) in patients following cytotoxic therapies is highly suggestive of an emerging therapy-related myeloid neoplasm. In this study, we describe 39 patients who acquired del(7q) as a sole abnormality in their bone marrow following cytotoxic therapies for malignant neoplasms. The median interval from cytotoxic therapies to detection of del(7q) was 40 months (range, 4-190 months). Twenty-eight patients showed an interstitial and 11 showed a terminal 7q deletion. Fifteen patients (38%) had del(7q) as a large clone and 24 (62%) as a small clone. With a median followup of 21 months (range, 1-135 months), 18 (46%) patients developed therapy-related myeloid neoplasms, including all 15 patients with a large del(7q) clone and 3/24 (12.5%) with a small clone. Of the remaining 21 patients with a small del(7q) clone, 16 showed no evidence of therapy-related myeloid neoplasms and 5 had an inconclusive pathological diagnosis. We conclude that isolated del(7q) emerging in patients after cytotoxic therapy may not always be associated with therapy-related myeloid neoplasms in about half of patients. The clone size of del(7q) is critical; a large clone is almost always associated with therapy-related myeloid neoplasms, whereas a small clone can be a clinically indolent or transient finding. Abnormalities of chromosome 7, either monosomy (−7) or deletion of the long arm (del(7q)), are the most common cytogenetic abnormalities detected in acute myeloid leukemia and myelodysplastic syndromes. 1-3 Del(7q)/ − 7 occurs in~8% of de novo acute myeloid leukemia and~10% of de novo myelodysplastic syndromes. 1,4 Del(7q) has been classified as the intermediate-II risk group in de novo acute myeloid leukemia 5 and the intermediate risk group in de novo myelodysplastic syndromes, respectively. 6 Therapy-related myeloid neoplasm is a late complication of cytotoxic therapies for primary malignant and non-malignant diseases. Cytogenetic abnormalities can be detected in more than 90% of patients with therapy-related myeloid neoplasms, and more than half of these patients have a complex karyotype. 7 Del(7q)/ − 7 presents in~50% of patients with therapy-related myeloid neoplasms and are often associated with prior exposure to alkylating agents or ionizing radiation. 1,[8][9][10][11][12][13] Any newly emerged cytogenetic abnormalities in patients with a prior history of cytotoxic therapies often raises the concern of development of therapy-related myeloid neoplasms, especially when the abnormalities include del(7q)/ − 7.In our practice, we have observed that some patients develop isolated del(7q) in their bone marrow following cytotoxic therapies, yet never develop therapy-related myeloid neoplasms with close follow-up. In order to better understand the

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Section: Discussionmentioning

confidence: 99%

Section: Follow-up and Outcomesmentioning

confidence: 99%

Newly emerged isolated Del(7q) in patients with prior cytotoxic therapies may not always be associated with therapy-related myeloid neoplasms

et al. 2016

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“…39,40 In addition, loss of Ezh2 in mouse hematopoietic stem cells is sufficient to cause aggressive T-acute lymphoblastic leukemia. 21,22 These studies demonstrate that the loss rather than overexpression of EZH2 may also contribute to tumorigenesis in myeloid and some lymphoid neoplasms, presumably through derepression of oncogenes owing to lack of H3K27 methylation.…”

Section: Discussionmentioning

confidence: 99%

“…19,20 Interestingly, there is also evidence that loss-offunction mutations and deletions of EZH2 and associated genes leads to the development of mouse and human T-acute lymphoblastic leukemia, suggesting that EZH2 functions as a tumor-suppressor gene for this hematopoietic neoplasm. 21,22 Because of the complicated role of EZH2 in the development of non-hematological as well as hematological malignancies, we investigated the expression of EZH2 in a range of small cell and aggressive B-cell non-Hodgkin lymphomas. We found that EZH2 expression correlates with aggressive behavior and with the expression of specific signaling molecules in aggressive B-cell lymphomas that are known to cause EZH2 overexpression and contribute to oncogenesis.…”

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confidence: 99%

Differential expression of enhancer of zeste homolog 2 (EZH2) protein in small cell and aggressive B-cell non-Hodgkin lymphomas and differential regulation of EZH2 expression by p-ERK1/2 and MYC in aggressive B-cell lymphomas

et al. 2016

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EZH2, a member of the polycomb protein group, is an important methyltransferase that is overexpressed in various neoplasms. We found that in small cell B-cell lymphomas, EZH2 is expressed in o 40% of neoplastic cells, with heterogenous signal intensity. In aggressive B-cell lymphomas, 70-100% of tumor cells were positive for EZH2 expression with high signal intensity, which correlated with a high proliferation rate. We investigated the potential signaling molecules that regulate EZH2 overexpression in aggressive B-cell lymphomas and found that 80% of cases of EZH2-positive diffuse large B-cell lymphoma show high p-ERK1/2 expression (average~57% tumor cell positivity). In contrast, only a small percentage of tumor cells (~10%) show p-ERK1/2 expression in Burkitt lymphoma and double hit lymphoma. On average, 91 and 76% of neoplastic cells were positive for MYC expression in Burkitt lymphoma and double hit lymphoma, respectively, while only 20% neoplastic cells were positive for MYC expression in diffuse large B-cell lymphoma. None of the aggressive B-cell lymphomas showed significant p-STAT3 expression in EZH2-overexpressed cases. The correlation of EZH2 expression with aggressive behavior and proliferation rate in B-cell neoplasms suggests that this molecule may function as an oncogenic protein in these neoplasms, with possible regulation by different signaling cascades in different types of aggressive B-cell lymphomas: p-ERK-related signaling in diffuse large B-cell lymphoma, and MYC-related signaling in Burkitt lymphoma and double hit lymphoma. Furthermore, EZH2 and associated signaling cascades may serve as therapeutic targets for the treatment of aggressive B-cell lymphomas. EZH2 is an important enzymatic subunit of the epigenetic regulator polycomb repressive complex 2 (PRC2) and functions as a methytransferase that targets the lysine 27 of histone H3 and controls gene silencing through posttranslational modification. 1 EZH2 is frequently overexpressed in various nonhematological malignancies and functions as an oncogenic protein for tumor cell proliferation, metastasis, and survival. 2 A number of intracytoplasmic oncogenic signaling molecules, transcription factors, and tumor-suppressor miRNAs regulate EZH2 expression in these non-hematological neoplasms. In the triple-negative and ERBB2-overexpressing aggressive subtypes of breast cancer, studies using promoter analysis and in vitro inhibitor methods demonstrated that the MEK/ERK/Elk-1 signaling pathway leads to EZH2 overexpression. 3 In a subset of invasive breast carcinomas and moderately to poorly differentiated non-small cell lung cancers, AKT(Ser473) phosphorylation was closely associated with EZH2 overexpression. 4,5 In prostate and hepatocellular carcinomas, upregulation of MYC protein results in the overexpression of EZH2 through reduction of miR-26a, miR26b, and miR-101. In addition, MYC can directly bind to and activate the EZH2 promoter. [6][7][8]

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“…In mouse somatic cloned embryos, inadequate expression of Ezh2 in inner cell mass (ICM) cells led to defective chromatin structure, particularly inadequate H3K27me3 (Zhang et al, 2009). In mouse and human, T-cell leukemia development was suppressed by Ezh2 and its associated genes (Simon et al, 2012). Moreover, Ezh2 is thought to be a therapeutic target for treating cancer (Qi et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

H3K27me3 may be associated with Oct4 and Sox2 in mouse preimplantation embryos

Zhang

Ding

et al. 2014

Genet. Mol. Res.

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ABSTRACT. As a core member of polycomb repressive complex 2, the transcription and enzyme activity of enhancer of zeste homolog 2 (Ezh2) is directly involved in the trimethylation of lysine 27 on histone H3. In this study, the fluorescence intensity of H3K27me3 in mouse in vivo morulae and blastocysts was compared by indirect immunofluorescence staining. We found that demethylation of H3K27me3 occurred during the blastocyst stage. Real-time polymerase chain reaction was performed to investigate Ezh2 expression in oocytes and in preimplantation embryos. Ezh2 expression peaked during the zygote stage and gradually decreased from the 2-cell stage, exhibiting an inverse pattern when compared with Oct4 and Sox2 mRNA in mouse preimplantation embryos. To understand the role of developmentrelated genes on the transcription of mouse Ezh2, a promoter assay was performed in NIH/3T3 cells. Ezh2 expression was markedly suppressed by Oct4 and Sox2 alone in a dose-dependent manner, while Ezh2 promoter activity in co-transfection with Nanog, Klf-4, and c-Myc groups showed no significant change as compared with the control. Our data suggest that the demethylation of H3K27me3 is caused by the degressive expression and activity of Ezh2 in blastocysts, leading to increased expression of developmentally important transcription factors. We also observed negative effects of Oct4 and Sox2 on the transcription of Ezh2 and identified Oct4 and Sox2 as novel negative regulators of Ezh2 at the post-translation level in a mouse preimplantation embryo.

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A key role for EZH2 and associated genes in mouse and human adult T-cell acute leukemia

Cited by 248 publications

References 28 publications

Newly emerged isolated Del(7q) in patients with prior cytotoxic therapies may not always be associated with therapy-related myeloid neoplasms

Newly emerged isolated Del(7q) in patients with prior cytotoxic therapies may not always be associated with therapy-related myeloid neoplasms

Differential expression of enhancer of zeste homolog 2 (EZH2) protein in small cell and aggressive B-cell non-Hodgkin lymphomas and differential regulation of EZH2 expression by p-ERK1/2 and MYC in aggressive B-cell lymphomas

H3K27me3 may be associated with Oct4 and Sox2 in mouse preimplantation embryos

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