Gene expression profiling of Polycomb, Hox and Meis genes in patients with acute myeloid leukaemia

Grubach, Lykke; Juhl‐Christensen, Caroline; Rethmeier, Anita; Olesen, Lene; Aggerholm, Anni; Hokland, Peter; Østergaard, Mette

doi:10.1111/j.1600-0609.2008.01083.x

Cited by 84 publications

(88 citation statements)

References 48 publications

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“…Overexpression of EZH2 has been reported in patients with high-risk MDS, MDS-derived AML, and AML, particularly in patients with complex karyotypes. 15,35 The inhibitory effect of the knockdown of EZH2 and the similar effect of DZNep on AML cells further supports the oncogenic function of EZH2 in AML. 21,22,36 In the present study, we have shown that deletion of Ezh2 compromises the progression of AML severely by promoting the differentiation of AML cells.…”

Section: Discussionmentioning

confidence: 60%

Ezh2 augments leukemogenicity by reinforcing differentiation blockage in acute myeloid leukemia

Tanaka

Miyagi

Sashida³

et al. 2012

Blood

170

136

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EZH2, a catalytic component of the polycomb repressive complex 2, trimethylates histone H3 at lysine 27 (H3K27) to repress the transcription of target genes. Although EZH2 is overexpressed in various cancers, including some hematologic malignancies, the role of EZH2 in acute myeloid leukemia (AML) has yet to be examined in vivo. In the present study, we transformed granulocyte macrophage progenitors from Cre-ERT;Ezh2 flox/flox mice with the MLL-AF9 leukemic fusion gene to analyze the function of Ezh2 in AML.Deletion of Ezh2 in transformed granulocyte macrophage progenitors compromised growth severely in vitro and attenuated the progression of AML significantly in vivo. Ezh2-deficient leukemic cells developed into a chronic myelomonocytic leukemia-like disease with a lower frequency of leukemia-initiating cells compared with the control. Chromatin immunoprecipitation followed by sequencing revealed a significant reduction in the levels of trimethylation at H3K27 in Ezh2-deficient leukemic cells, not only at Cdkn2a, a known major target of Ezh2, but also at a cohort of genes relevant to the developmental and differentiation processes. Overexpression of Egr1, one of the derepressed genes in Ezh2-deficient leukemic cells, promoted the differentiation of AML cells profoundly. Our findings suggest that Ezh2 inhibits differentiation programs in leukemic stem cells, thereby augmenting their leukemogenic activity. IntroductionThe polycomb group (PcG) of proteins function in gene silencing through histone modifications, forming the chromatin-associated multiprotein complexes known as polycomb repressive complex 1 (PRC1) and PRC2. These 2 complexes work together to maintain heritable chromatin modifications, mediating transcriptional repression of target genes, 1 and have been characterized as general regulators of stem cells.Among the PcG proteins, BMI1, a core component of PRC1, plays an essential role in the maintenance of the self-renewal ability of hematopoietic stem cells (HSCs), at least partially by silencing the CDKN2A (INK4A/ARF) locus. 2-5 BMI1 also maintains the multipotency of HSCs by keeping developmental regulator gene promoters poised for activation. 6 EZH2 is a catalytic component of PRC2 that trimethylates histone H3 at lysine 27 (H3K27) to repress its target genes transcriptionally. We recently reported that Ezh2 is essential for fetal but not adult HSCs. 7 Ezh2-deficient embryos die of anemia because of insufficient expansion of hematopoietic stem/progenitor cells and defective erythropoiesis in the fetal liver. Deletion of Ezh2 in adult BM perturbs lymphopoiesis but does not otherwise affect hematopoiesis. 7-9 Ezh1 has been shown to compensate for Ezh2 deficiency in mouse embryonic stem cells, 10 and may also act in a compensatory fashion in Ezh2-deficient BM HSCs. 7 In contrast, overexpression of Ezh2 in HSCs reportedly prevents exhaustion of the long-term repopulating potential of HSCs during repeated serial transplantation. 11PcG genes have also been linked to cancer. 12-14 Aberrant regulation of E...

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Section: Discussionmentioning

confidence: 60%

Ezh2 augments leukemogenicity by reinforcing differentiation blockage in acute myeloid leukemia

Tanaka

Miyagi

Sashida³

et al. 2012

Blood

170

136

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“…These findings support earlier reports that point to a role of HOX and Polycomb as target genes in leukemia. 35 In addition, another major objective of our study was to determine whether patterns of DNA methylation could be used to improve patient prognostication. Using a semisupervised approach, 31 we were able to build a predictive model based on quantitative methylation patterns.…”

Section: Discussionmentioning

confidence: 99%

Quantitative DNA methylation predicts survival in adult acute myeloid leukemia

Bullinger

Ehrich

Döhner

et al. 2010

Blood

147

117

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Acute myeloid leukemia (AML) is characterized by molecular heterogeneity that is not fully reflected in the current classification system. Recent insights point toward a significant role of aberrant DNA methylation in leukemogenesis. Therefore, we investigated the prognostic impact of DNA methylation in AML. To screen for promoter methylation in AML we applied a combination of base-specific cleavage biochemistry and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS), a powerful methodology allowing for quantitatively investigating DNA methylation status in a large series of both promoter regions and leukemia samples. We analyzed 92 genomic regions in 182 patient samples, correlated findings with clinical and molecular data, and validated the results in an independent cohort of 74 AML samples. Using this approach, we were able to identify novel leukemia subgroups based on distinct DNA methylation patterns. Furthermore, we defined a methylation-based outcome predictor for patient survival (P < .01) that in multivariable analysis provided independent prognostic information (hazard ratio, 1.52; 95% CI, 1.06-2.16). Here, we report the first large-scale methylation-based outcome predictor in AML, and thereby our findings support the use of genomic methylation markers for improved molecular classification and prognostication in adult AML. (Blood. 2010;115:636-642)

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“…23 The authors, using different approaches, demonstrated that YY1 is overexpressed in osteosarcoma cell lines and tissues compared to normal osteoblastic cells with a predominant localization in the nucleus. 23 High levels of YY1 were observed in non-solid tumors, including myeloid leukemia (AML), 24 Hodgkin lymphoma (HD) 25 and Non-Hodgkin lymphoma (NHL), 26,27 when compared to normal samples. Sakhinia et al 26 showed that YY1 was upregulated in follicular lymphoma (FL) and in diffuse large B-cell lymphoma (DLBCL).…”

Section: Implication Of Yin Yang 1 In Response To Therapeutic-inducedmentioning

confidence: 99%

The involvement of the transcription factor Yin Yang 1 in cancer development and progression

Castellano¹,

Torrisi²,

Ligresti³

et al. 2009

Cell Cycle

117

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The Yin Yang 1 (YY1) transcription factor has a pivotal role in normal biological processes such as development, differentiation, replication and cell proliferation exerting its effects on a huge number of genes involved in these processes. Mechanisms of YY1 action are related to its ability to initiate, activate, or repress transcription depending upon the context in which it binds. The role of YY1 played in cancer has been recently explored. This article summarizes the most relevant studies focused on YY1 regulation and dwells on the way how its overexpression may affect the clinical behavior of several cancer types. Furthermore, the contribution of the upregulation of YY1 exerted in response to therapeutic-induced apoptosis is discussed.

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Gene expression profiling of Polycomb, Hox and Meis genes in patients with acute myeloid leukaemia

Cited by 84 publications

References 48 publications

Ezh2 augments leukemogenicity by reinforcing differentiation blockage in acute myeloid leukemia

Ezh2 augments leukemogenicity by reinforcing differentiation blockage in acute myeloid leukemia

Quantitative DNA methylation predicts survival in adult acute myeloid leukemia

The involvement of the transcription factor Yin Yang 1 in cancer development and progression

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