Correlation between Hypomethylation of DNA and Expression of Globin Genes in Friend Erythroleukemia Cells

Christman, Judith K.; Price, Peter M.; Pedrinan, Lauri; Acs, George

doi:10.1111/j.1432-1033.1977.tb11926.x

Cited by 202 publications

(83 citation statements)

References 60 publications

(6 reference statements)

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“…McGhee & Ginder (1979) have shown that in adult reticulocytes and erythrocytes which are expressing or have expressed the adult P-globin gene, CCGG sites near the ends of the gene sequence are unmethylated, whereas in oviduct, brain and embryonic red blood cells, which do not express this gene, such sites are at least partially methylated. Christman et al (1977) found that DNA isolated from Friend erythroleukaemic cells induced to produce globin mRNA is hypomethylated when compared to DNA from uninduced cells. demonstrated the existence of a class of methylation sites (mvar) within and around the conalbumin, ovomucoid, and ,B-globin genes, the variable methylation of which correlated with transcriptional activity.…”

Section: Enzymatic Methylation In Gene Expressionmentioning

confidence: 99%

5-Methylcytosine depletion during tumour development: An extension of the miscoding concept

Nyce¹,

Weinhouse²,

Magee³

1983

Br J Cancer

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Perhaps the most ubiquitous aspect of tumours and the neoplastic cells of which they are composed is their loss of the ability to control cellular functions in a normal way. During the development of the malignant state, the neoplastic cell becomes increasingly refractory to both the internal and external stimulae which integrate its normal counterparts into functional tissues and organ systems. This lack of integration is associated with alterations in the expression of a host of gene products, including, for example, the ectopic biosynthesis of hormones (

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Section: Enzymatic Methylation In Gene Expressionmentioning

confidence: 99%

5-Methylcytosine depletion during tumour development: An extension of the miscoding concept

Nyce¹,

Weinhouse²,

Magee³

1983

Br J Cancer

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“…The theory I have outlined can thus explain the carcinogenic activity of ethionine, because its presence in dividing cells could lead to the loss of methylation in controlling sequences. Recently it has been shown that ethionine can stimulate the in vitro differentiation of Friend cells (Christman et at., 1977) and that this is related to a reduction in DNA methylation.…”

Section: Effects Of Ethionine Promotors and Bromodeoxyuridinementioning

confidence: 99%

“…Although such modifications could in principle involve actual changes in base sequences we (Holliday & Pugh, 1975), were also able to explain how the specific methylation of bases such as adenine or cytosine could provide epigenetic switches in gene activity. Recently it has been shown that the differentiation of Friend erythroleukaemic cells in vitro is related to the extent of DNA methylation (Christman et al, 1977). One possible switch mechanism is illustrated in Fig.…”

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confidence: 99%

A new theory of carcinogenesis

Holliday¹

1979

Br J Cancer

191

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Summary.-Although many carcinogens are mutagens, there is no direct evidence that the cancer-cell phenotype is the result of gene mutation. Transplantation experiments have strongly indicated that malignant cells can arise or revert to the normal phenotype in the absence of mutation. It is suggested that damage to DNA followed by repair triggers the epigenetic changes in gene expression which are responsible for malignancy. We previously proposed that methylation of specific DNA sequences adjacent to structural genes determines whether or not transcription will occur. Specific methylases are required for the switching on of genes and for the stable maintenance of the methylated state, which provides a basis for the control of gene expression in differentiated cells. It is now seen that damage to DNA followed by repair, just before or just after DNA replication, can lead to the loss of methyl groups. This can induce a switch in gene activity which is heritable, but potentially reversible. The known large difference in the probability of malignant transformation in cells of rodents and large mammals is hard to explain if mutation is responsible. On the other hand, this new theory provides an explanation for this difference, since the probability of epigenetic changes in gene activity will depend on the activity of methylating enzymes and the rate of excision repair. The theory is supported by the evidence that excision repair is more efficient in cultured fibroblasts from large long-lived animals than from small short-lived ones.

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“…4 In vitro exposure of an erythroleukemic cell line to azacitidine resulted in induction of differentiation. 5 Presumably this effect was related to hypomethylation of the DNA. Earlier clinical studies demonstrated activity of high-dose intravenous azacitidine in patients with AML.…”

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confidence: 99%

Treatment of acute myelogenous leukemia with outpatient azacitidine

Sudan

Rossetti

Shadduck

et al. 2006

Cancer

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BACKGROUNDPatients older than 55 years of age with acute myelogenous leukemia (AML) are less likely to achieve complete remission and more likely to experience toxicity with conventional induction chemotherapy than younger patients. Azacitidine administered in the outpatient setting is well tolerated and can induce complete hematological remission in patients with myelodysplastic syndromes (MDS). At higher doses, azacitidine has activity in AML.METHODSTwenty patients were retrospectively identified who had been treated with azacitidine with bone marrow blast counts between 21 and 38%. Patients with blast counts up to 29% were initially treated as MDS, but by WHO now meet criteria for AML. Patients with blast counts over 29% were treated with azacitidine after being deemed poor candidates for induction chemotherapy. Azacitidine 75 mg/m2/day was administered subcutaneously for 7 days every 4 weeks, which was defined as 1 cycle.RESULTSThe overall response rate was 60% (12/20): complete response (CR; n = 4; 20%); partial response (PR; n = 5; 25%); hematologic improvement (HI; n = 3; 15%). The median survival of responders was 15+ months compared with 2.5 months for nonresponders (P = .009). During therapy, responders had an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or 0. The most common toxic event was infection (n = 8). Four patients were hospitalized during the first cycle of treatment.CONCLUSIONSAzacitidine administered in the outpatient setting can induce remission in AML. The therapy is well tolerated and might be an alternative for patients unlikely to tolerate standard induction chemotherapy. Cancer 2006. © 2006 American Cancer Society.

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Correlation between Hypomethylation of DNA and Expression of Globin Genes in Friend Erythroleukemia Cells

Cited by 202 publications

References 60 publications

5-Methylcytosine depletion during tumour development: An extension of the miscoding concept

5-Methylcytosine depletion during tumour development: An extension of the miscoding concept

A new theory of carcinogenesis

Treatment of acute myelogenous leukemia with outpatient azacitidine

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