Targeting Hypomethylation of DNA to Achieve Cellular Differentiation in Myelodysplastic Syndromes (MDS)

Silverman, L.R.

doi:10.1634/theoncologist.6-2004-8

Cited by 10 publications

(16 citation statements)

References 13 publications

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“…The significant spectral differences found over a substantial portion of the spectral range clearly demonstrate that the transformation of the control granulocyte DNA to the MDS structure involves readily discernable alterations in both the nucleotide bases and backbone. The differences in the cytosine peaks for the control and MDS samples at 1,651 cm Ϫ1 may well arise from methylation reactions (2,12). Because patients were not on medications known to affect DNA methylation, it is reasonable to speculate that the observed differences in cytosine vibrations between the groups may be a consequence of this reaction (7)(8)(9), although other factors cannot be ruled out.…”

Section: Resultsmentioning

confidence: 96%

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confidence: 99%

“…It is estimated that 15,000 to 20,000 cases of MDS are diagnosed each year in the United States, primarily in patients over 60 years of age (2,3), most of whom die of infection or bleeding. Moreover, up to 40% of cases transform to acute myelogenous leukemia (2,4). Only half of MDS cases are characterized by nonrandom chromosomal abnormalities, and for the rest diagnosis is largely dependent on the presence of blood count suppression in association with morphologic abnormalities of both mature and immature myeloid cells (5,6).…”

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Models of granulocyte DNA structure are highly predictive of myelodysplastic syndrome

Malins

Anderson

Polissar

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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We have used statistical models based on Fourier transforminfrared spectra to differentiate between the DNA structure of normal granulocytes and those obtained from patients with myelodysplastic syndrome (MDS). The substantial degree of discrimination achieved between the two DNA groups is attributed to differences in the nucleotide base and backbone structures. These structural differences allowed for the development of a discriminant analysis model that predicted, with high sensitivity and specificity, which DNA came from normal granulocytes vs. granulocytes from MDS patients. The findings are a promising basis for developing a blood test to diagnose and predict the occurrence of MDS, for which there is currently a paucity of molecular markers.clonal blood disease ͉ blood test ͉ disease diagnosis and prediction ͉ Fourier transform-infrared spectroscopy M yelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disorder characterized by peripheral blood cytopenias caused by ineffective hematopoiesis that can lead to bone marrow failure (1). It is estimated that 15,000 to 20,000 cases of MDS are diagnosed each year in the United States, primarily in patients over 60 years of age (2, 3), most of whom die of infection or bleeding. Moreover, up to 40% of cases transform to acute myelogenous leukemia (2, 4). Only half of MDS cases are characterized by nonrandom chromosomal abnormalities, and for the rest diagnosis is largely dependent on the presence of blood count suppression in association with morphologic abnormalities of both mature and immature myeloid cells (5, 6). As a consequence of this phenotypic mimicry, the distinction between MDS and nonclonal disorders causing bone marrow failure is often difficult.Although the molecular basis of MDS remains to be clarified, it is recognized that aberrant DNA hypermethylation is one event implicated in the transformation of MDS to acute myelogenous leukemia (7-9). This reaction, which is catalyzed by DNA methyltransferase enzymes (10), has been shown to favor promoter-associated CpG-rich regions (CpG islands) of the DNA (8, 11-13). The methylation of cytosine and certain other epigenetic events (e.g., reactions of oxygen free radicals; ref. 14) leading to base modifications would be expected to interfere with the normal vertical base stacking properties of DNA, which, in turn, would induce conformational changes in the phosphodiester-deoxyribose backbone (15, 16). These structural alterations are likely to affect the fidelity of DNA replication and transcription (17,18).We previously have demonstrated that highly sensitive statistical models of Fourier transform-infrared (FT-IR) spectra are capable of identifying subtle differences in the base and backbone structures of DNA in normal and abnormal tissues. This technology has been used successfully to discriminate between DNA structures of the normal and cancerous breast (19-23) and prostate (24,25). The structural differences were the basis for constructing statistical models that predict the probability of ca...

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Section: Resultsmentioning

confidence: 96%

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confidence: 99%

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confidence: 99%

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Models of granulocyte DNA structure are highly predictive of myelodysplastic syndrome

Malins

Anderson

Polissar

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…Progress in the understanding of myeloproliferative disorders and myelodysplasia has lead to the initiation of clinical trials for this agent in these disorders, as discussed in the article by Dr. Lewis Silverman [9]. Although not immediately obvious candidates for use in hematologic malignancies, the highly publicized and anticipated angiogenesis inhibitors also have considerable promise [10].…”

Section: Hypomethylating Agentsmentioning

confidence: 99%

Hematologic Malignancies: An Opportunity for Targeted Drug Therapy

Gabrilove

2001

The Oncologist

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“…[5][6][7][8][9] Azacitidine is believed to exert its antineoplastic effects, in part, by inducing DNA hypomethylation. [10][11][12][13][14] Induction of DNA hypomethylation may restore normal function to genes that are critical for differentiation and proliferation. 5,15,16 The goal of pharmaceutical intervention is to provide maximum therapeutic effectiveness with minimum risk to subjects.…”

Section: Introductionmentioning

confidence: 99%