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Aberrant DNA Methylation Is Associated with a Poor Outcome in Juvenile Myelomonocytic Leukemia.

Sakaguchi H, Muramatsu H, Okuno Y, Makishima H, Xu Y, Furukawa-Hibi Y, Wang X, Narita A, Yoshida K, Shiraishi Y, Doisaki S, Yoshida N, Hama A, Takahashi Y, Yamada K, Miyano S, Ogawa S, Maciejewski JP, Kojima S - PLoS ONE (2015)

Bottom Line: Among 16 candidate genes, BMP4, CALCA, CDKN2A, and RARB exhibited significant hypermethylation in 72% (67/92) of patients.In the AMS 3-4 cohort, 5-year OS and TFS were markedly low (8% and 0%, respectively).For patients with AMS 3-4 in whom hematopoietic stem cell transplantation does not improve the prognosis, alternative therapies, including DNA methyltransferase inhibitors and new molecular-targeting agents, should be established as treatment options.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.

ABSTRACT
Juvenile myelomonocytic leukemia (JMML), an overlap of myelodysplastic / myeloproliferative neoplasm, is an intractable pediatric myeloid neoplasm. Epigenetic regulation of transcription, particularly by CpG methylation, plays an important role in tumor progression, mainly by repressing tumor-suppressor genes. To clarify the clinical importance of aberrant DNA methylation, we studied the hypermethylation status of 16 target genes in the genomes of 92 patients with JMML by bisulfite conversion and the pryosequencing technique. Among 16 candidate genes, BMP4, CALCA, CDKN2A, and RARB exhibited significant hypermethylation in 72% (67/92) of patients. Based on the number of hypermethylated genes, patients were stratified into three cohorts based on an aberrant methylation score (AMS) of 0, 1-2, or 3-4. In the AMS 0 cohort, the 5-year overall survival (OS) and transplantation-free survival (TFS) were good (69% and 76%, respectively). In the AMS 1-2 cohort, the 5-year OS was comparable to that in the AMS 0 cohort (68%), whereas TFS was poor (6%). In the AMS 3-4 cohort, 5-year OS and TFS were markedly low (8% and 0%, respectively). Epigenetic analysis provides helpful information for clinicians to select treatment strategies for patients with JMML. For patients with AMS 3-4 in whom hematopoietic stem cell transplantation does not improve the prognosis, alternative therapies, including DNA methyltransferase inhibitors and new molecular-targeting agents, should be established as treatment options.

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Summary of DNA methylation in candidate genes.(A) The dot plot represents the frequencies of methylated CpG sites for each candidate gene in the 92 patients with juvenile myelomonocytic leukemia. Aberrant hypermethylation was defined as >3 standard deviations above the mean methylation level of the healthy control population. The threshold values of each gene are shown as red broken lines. (B) Kaplan–Meier plots of the patient groups, defined by aberrant methylation of the indicated genes, are shown for BMP4, CALCA, CDKN2A, CDKN2B, H19, and RARB.
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pone.0145394.g001: Summary of DNA methylation in candidate genes.(A) The dot plot represents the frequencies of methylated CpG sites for each candidate gene in the 92 patients with juvenile myelomonocytic leukemia. Aberrant hypermethylation was defined as >3 standard deviations above the mean methylation level of the healthy control population. The threshold values of each gene are shown as red broken lines. (B) Kaplan–Meier plots of the patient groups, defined by aberrant methylation of the indicated genes, are shown for BMP4, CALCA, CDKN2A, CDKN2B, H19, and RARB.

Mentions: Among 16 candidate genes, aberrant hypermethylation of BMP4 (41/92, 45%), CALCA (32/92, 35%), CDKN2A (32/92, 35%), CDKN2B (4/92, 4%), H19 (5/92, 5%), and RARB (13/92, 14%) was detected in our cohort (Fig 1A). For the other 10 genes, no hypermethylation exceeding the limit of detection was observed. Hypermethylation of BMP4, CALCA, CDKN2A, and RARB in particular, resulted in a poorer outcome as indicated by the Kaplan–Meier estimates for TFS, for which the probabilities of TFS for patients with and without methylation were: 31% and 0% (p <0.001), for BMP4; 25% and 4% (p = 0.07), for CALCA; 25% and 0% (p <0.001), for CDKN2A; and 22% and 0% (p = 0.04), for RARB, respectively (Fig 1B).


Aberrant DNA Methylation Is Associated with a Poor Outcome in Juvenile Myelomonocytic Leukemia.

Sakaguchi H, Muramatsu H, Okuno Y, Makishima H, Xu Y, Furukawa-Hibi Y, Wang X, Narita A, Yoshida K, Shiraishi Y, Doisaki S, Yoshida N, Hama A, Takahashi Y, Yamada K, Miyano S, Ogawa S, Maciejewski JP, Kojima S - PLoS ONE (2015)

Summary of DNA methylation in candidate genes.(A) The dot plot represents the frequencies of methylated CpG sites for each candidate gene in the 92 patients with juvenile myelomonocytic leukemia. Aberrant hypermethylation was defined as >3 standard deviations above the mean methylation level of the healthy control population. The threshold values of each gene are shown as red broken lines. (B) Kaplan–Meier plots of the patient groups, defined by aberrant methylation of the indicated genes, are shown for BMP4, CALCA, CDKN2A, CDKN2B, H19, and RARB.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4697810&req=5

pone.0145394.g001: Summary of DNA methylation in candidate genes.(A) The dot plot represents the frequencies of methylated CpG sites for each candidate gene in the 92 patients with juvenile myelomonocytic leukemia. Aberrant hypermethylation was defined as >3 standard deviations above the mean methylation level of the healthy control population. The threshold values of each gene are shown as red broken lines. (B) Kaplan–Meier plots of the patient groups, defined by aberrant methylation of the indicated genes, are shown for BMP4, CALCA, CDKN2A, CDKN2B, H19, and RARB.
Mentions: Among 16 candidate genes, aberrant hypermethylation of BMP4 (41/92, 45%), CALCA (32/92, 35%), CDKN2A (32/92, 35%), CDKN2B (4/92, 4%), H19 (5/92, 5%), and RARB (13/92, 14%) was detected in our cohort (Fig 1A). For the other 10 genes, no hypermethylation exceeding the limit of detection was observed. Hypermethylation of BMP4, CALCA, CDKN2A, and RARB in particular, resulted in a poorer outcome as indicated by the Kaplan–Meier estimates for TFS, for which the probabilities of TFS for patients with and without methylation were: 31% and 0% (p <0.001), for BMP4; 25% and 4% (p = 0.07), for CALCA; 25% and 0% (p <0.001), for CDKN2A; and 22% and 0% (p = 0.04), for RARB, respectively (Fig 1B).

Bottom Line: Among 16 candidate genes, BMP4, CALCA, CDKN2A, and RARB exhibited significant hypermethylation in 72% (67/92) of patients.In the AMS 3-4 cohort, 5-year OS and TFS were markedly low (8% and 0%, respectively).For patients with AMS 3-4 in whom hematopoietic stem cell transplantation does not improve the prognosis, alternative therapies, including DNA methyltransferase inhibitors and new molecular-targeting agents, should be established as treatment options.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.

ABSTRACT
Juvenile myelomonocytic leukemia (JMML), an overlap of myelodysplastic / myeloproliferative neoplasm, is an intractable pediatric myeloid neoplasm. Epigenetic regulation of transcription, particularly by CpG methylation, plays an important role in tumor progression, mainly by repressing tumor-suppressor genes. To clarify the clinical importance of aberrant DNA methylation, we studied the hypermethylation status of 16 target genes in the genomes of 92 patients with JMML by bisulfite conversion and the pryosequencing technique. Among 16 candidate genes, BMP4, CALCA, CDKN2A, and RARB exhibited significant hypermethylation in 72% (67/92) of patients. Based on the number of hypermethylated genes, patients were stratified into three cohorts based on an aberrant methylation score (AMS) of 0, 1-2, or 3-4. In the AMS 0 cohort, the 5-year overall survival (OS) and transplantation-free survival (TFS) were good (69% and 76%, respectively). In the AMS 1-2 cohort, the 5-year OS was comparable to that in the AMS 0 cohort (68%), whereas TFS was poor (6%). In the AMS 3-4 cohort, 5-year OS and TFS were markedly low (8% and 0%, respectively). Epigenetic analysis provides helpful information for clinicians to select treatment strategies for patients with JMML. For patients with AMS 3-4 in whom hematopoietic stem cell transplantation does not improve the prognosis, alternative therapies, including DNA methyltransferase inhibitors and new molecular-targeting agents, should be established as treatment options.

Show MeSH
Related in: MedlinePlus