Promoter methylation of DAPK1, E-cadherin and thrombospondin-1 in de novo and therapy-related myeloid neoplasms

Greco, Mariangela; D’Alo’, Francesco; Scardocci, Alessandra; Criscuolo, Marianna; Fabiani, Emiliano; Guidi, Francesco; Ruscio, Annalisa Di; Migliara, Giuseppe; Pagano, Livio; Fianchi, Luana; Chiusolo, Patrizia; Hohaus, Stefan; Leone, Giuseppe; Voso, Maria Teresa

doi:10.1016/j.bcmd.2010.05.008

Cited by 30 publications

(23 citation statements)

References 26 publications

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“…[24] In additional, prior cytotoxic exposure often cause additional damage at the cellular and DNA level of hematopoietic cells; and these underlying genetic/epigenetic alterations likely explain chemo-resistance and poor responses to conventional therapy in t-MDS. [14,13,15,16] It has been known that in t-MDS, many of the well-known risk factors for primary MDS, such as morphological dysplasia and a precise division of BM blasts, may not be so important. [17] Rather, the clinical and biological behavior of this group of diseases may largely depend on underlying genetic/epigenetic alterations.…”

Section: Discussionmentioning

confidence: 99%

The clinical importance of moderate/severe bone marrow fibrosis in patients with therapy-related myelodysplastic syndromes

Goswami

et al. 2013

Ann Hematol

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Background The presence of moderate to severe bone marrow (BM) fibrosis has been shown to be an adverse feature in patients with primary myelodysplastic syndromes (MDS). However, the clinical importance of BM fibrosis is not clear in therapy-related MDS. Methods We retrieved all t-MDS cases (n=266) diagnosed at our hospital over a 10-year period (2003–2012). Reticulin and trichromestains were performed in cases in which BM fibrosis was suspected on initial evaluation of hematoxylin & eosin stained slide. BM fibrosis was graded according to European consensus guidelines, and a score of MF2/MF3 was defined as moderate/severe fibrosis. Result Moderate/severe BM fibrosis was found in 47 (17%) patients. Compared to 219 patients with no/mild BM fibrosis, the patients with moderate/severe fibrosis presented with severer thrombocytopenia (p=0.039), higher numbers of circulating blasts (p=0.051) but similar degrees of anemia and neutropenia, transfusion requirements, and similar incidences of hepatosplenomegaly and constitutional symptoms. Histological examination revealed a comparable BM cellularity and BM blast percentage, but markedly increased megakaryocytes (p<0.001) in the fibrotic group. Although the risk distribution of cytogenetic data was similar according to the New Comprehensive Cytogenetic Scoring criteria, −5 and −17 were more frequently observed in t-MDS with moderate/severe BM fibrosis (p=0.031 and p=0.043 respectively). With a median follow-up of 11.5 months, patients with moderate/severe BM fibrosis showed a similar risk of acute myeloid leukemia transformation, and a comparable overall survival in univariate and multivariate analyses. Conclusions Moderate/severe BM fibrosis in patients with t-MDS is associated with certain clinicopathological and genetic features. However, unlike the situation in patients with primary MDS, moderate/severe BM fibrosis does not add additional risk to patients with therapy-related MDS.

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Section: Discussionmentioning

confidence: 99%

The clinical importance of moderate/severe bone marrow fibrosis in patients with therapy-related myelodysplastic syndromes

Goswami

et al. 2013

Ann Hematol

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“…It is mentioned as a typical tumor suppressor gene and plays a critical role in carcinogenesis. Loss expression of CDH1 enables disaggregation of cancer cells from one another and increases their metastatic potential [11,12]. However, the pattern of CDH1 expression and its clinical implication remain to be elucidated in AML.…”

Section: Introductionmentioning

confidence: 99%

“…Along with vimentin and N-cadherin, E-cadherin is one of the most well-known EMT marker genes. CDH1, located at 16q22.1 and encoding E-cadherin protein, is a member of trans-membrane glycoproteins that mediate calcium-dependent cell adhesion in embryonic development and in the maintenance of tissue architecture [10,11]. It is mentioned as a typical tumor suppressor gene and plays a critical role in carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

CDH1 (E-cadherin) expression independently affects clinical outcome in acute myeloid leukemia with normal cytogenetics

Zhang

Zhou

et al. 2016

Clinical Chemistry and Laboratory Medicine (CCLM)

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“…by guest www.bloodjournal.org From were previously shown to be methylated in AML primary samples or cell lines (eg, CDH1 and CDKN2B), or methylated in many somatic cells (eg, H19, MAGEA1, CTAG1B). [24][25][26][27] DAC treatment specifically increased the expression of highly methylated genes, such as H19, MAGEA1, and MAGEB2 ( Figure 2G, supplemental Table 4), but the expression of many genes also increased after AraC treatment. Although the expression changes were modest, these results suggested that this assay can be adapted to study the direct impact of DAC on primary AML samples without the confounding variable of concurrent differentiation.…”

Section: In Vitro Decitabine Treatment On Primary Aml Cells 1635mentioning

confidence: 99%

Genomic impact of transient low-dose decitabine treatment on primary AML cells

Klco¹,

Spencer²,

Lamprecht³

et al. 2013

Blood

138

131

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Key Points• Decitabine treatment of in vitro expanded primary AML samples leads to global hypomethylation.• Highly methylated CpGs are most affected by decitabineinduced hypomethylation, with little influence on transcriptional activity.Acute myeloid leukemia (AML) is characterized by dysregulated gene expression and abnormal patterns of DNA methylation; the relationship between these events is unclear. Many AML patients are now being treated with hypomethylating agents, such as decitabine (DAC), although the mechanisms by which it induces remissions remain unknown. The goal of this study was to use a novel stromal coculture assay that can expand primary AML cells to identify the immediate changes induced by DAC with a dose (100nM) that decreases total 5-methylcytosine content and reactivates imprinted genes (without causing myeloid differentiation, which would confound downstream genomic analyses). Using array-based technologies, we found that DAC treatment caused global hypomethylation in all samples (with a preference for regions with higher levels of baseline methylation), yet there was limited correlation between changes in methylation and gene expression. Moreover, the patterns of methylation and gene expression across the samples were primarily determined by the intrinsic properties of the primary cells, rather than DAC treatment. Although DAC induces hypomethylation, we could not identify canonical target genes that are altered by DAC in primary AML cells, suggesting that the mechanism of action of DAC is more complex than previously recognized. (Blood. 2013;121(9):1633-1643) IntroductionAcute myeloid leukemia (AML) is a clonal hematopoietic neoplasm characterized by maturation arrest in the myeloid lineage. Treatment typically consists of induction chemotherapy with an anthracycline and cytarabine with the goal of achieving a complete remission, 1,2 followed by consolidation therapy. Despite these measures, the mortality rate of AML is still very high. Although recent genomic advances have improved our understanding of AML pathogenesis and risk stratification 3,4 the overall outcome is still dismal for most patients, and alternative treatment strategies are needed.One alternative approach for the treatment of AML and myelodysplastic syndromes (MDS) is the use of hypomethylating agents, including the cytosine analogs 5-azacytidine (AZA) and 5-aza-2Ј-deoxycytidine (decitabine; DAC). 5,6 These nucleosides are distinct from other cytosine analogs because they contain a pyrimidine ring modification that results in the covalent trapping of the maintenance DNA methyltransferase (DNMT1). This effect is cell-cycle dependent, because AZA and DAC must first be modified and incorporated into newly synthesized DNA; this leads to passive hypomethylation of DNA as cells divide, because of the depletion and degradation of DNMT1. 7,8 Exposure to these drugs is also associated with cellular differentiation 9,10 and cytotoxicity at higher doses. 11 Although the impact of DAC and AZA on acute myeloid leukemia cell lines ha...

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Promoter methylation of DAPK1, E-cadherin and thrombospondin-1 in de novo and therapy-related myeloid neoplasms

Cited by 30 publications

References 26 publications

The clinical importance of moderate/severe bone marrow fibrosis in patients with therapy-related myelodysplastic syndromes

The clinical importance of moderate/severe bone marrow fibrosis in patients with therapy-related myelodysplastic syndromes

CDH1 (E-cadherin) expression independently affects clinical outcome in acute myeloid leukemia with normal cytogenetics

Genomic impact of transient low-dose decitabine treatment on primary AML cells

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