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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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Hypermethylation status and clinical outcome in patients with juvenile myelomonocytic leukemia (JMML).(A) Kaplan–Meier curves represent the probability of transplantation-free survival (TFS) in the 92 patients with JMML. TFS was defined as the probability of being alive and transplantation free. Both death and transplantation were considered events. The probability of 5-year TFS in the aberrant methylation score (AMS) 0 cohort (solid line) was significantly higher than that in the AMS 1–2 (long dashed line) and AMS 3–4 cohorts (dashed line), p < 0.001. (B) Kaplan–Meier curves represent the probability of overall survival (OS) in the 92 patients with JMML. Death was considered an event. The probability of OS in both the AMS 0 (solid line) and 1–2 cohorts (long dashed line) was significantly higher than that in the AMS 3–4 cohort (dashed line), p < 0.001.
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pone.0145394.g003: Hypermethylation status and clinical outcome in patients with juvenile myelomonocytic leukemia (JMML).(A) Kaplan–Meier curves represent the probability of transplantation-free survival (TFS) in the 92 patients with JMML. TFS was defined as the probability of being alive and transplantation free. Both death and transplantation were considered events. The probability of 5-year TFS in the aberrant methylation score (AMS) 0 cohort (solid line) was significantly higher than that in the AMS 1–2 (long dashed line) and AMS 3–4 cohorts (dashed line), p < 0.001. (B) Kaplan–Meier curves represent the probability of overall survival (OS) in the 92 patients with JMML. Death was considered an event. The probability of OS in both the AMS 0 (solid line) and 1–2 cohorts (long dashed line) was significantly higher than that in the AMS 3–4 cohort (dashed line), p < 0.001.

Mentions: The patients were classified into three cohorts according to the AMS score (Table 1 and Fig 3). The AMS 0 cohort displayed better survival without HSCT; specifically, the probabilities of 5-year TFS and OS in this cohort were 69% (95% CI, 45%–84%) and 76% (95% CI, 45%–91%), respectively. Patients in the AMS 1–2 cohort were rescued by HSCT. The probabilities of 5-year TFS and OS in this cohort were 6% (95% CI, 1%–17%) and 68% (95% CI, 50%–81%), respectively. In sharp contrast, the prognosis of patients in the AMS 3–4 cohort was not improved by HSCT, as the probabilities of 5-year TFS and OS in this cohort were 0% and 8% (95% CI, 0%–29%), respectively. Indeed, six of seven patients who received allogeneic HSCT in the AMS 3–4 cohort died during observation. Their causes of death consisted of progressive disease (n = 3), veno-occlusive disease (n = 2), and respiratory distress (n = 1), as shown in Table 2.


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)

Hypermethylation status and clinical outcome in patients with juvenile myelomonocytic leukemia (JMML).(A) Kaplan–Meier curves represent the probability of transplantation-free survival (TFS) in the 92 patients with JMML. TFS was defined as the probability of being alive and transplantation free. Both death and transplantation were considered events. The probability of 5-year TFS in the aberrant methylation score (AMS) 0 cohort (solid line) was significantly higher than that in the AMS 1–2 (long dashed line) and AMS 3–4 cohorts (dashed line), p < 0.001. (B) Kaplan–Meier curves represent the probability of overall survival (OS) in the 92 patients with JMML. Death was considered an event. The probability of OS in both the AMS 0 (solid line) and 1–2 cohorts (long dashed line) was significantly higher than that in the AMS 3–4 cohort (dashed line), p < 0.001.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0145394.g003: Hypermethylation status and clinical outcome in patients with juvenile myelomonocytic leukemia (JMML).(A) Kaplan–Meier curves represent the probability of transplantation-free survival (TFS) in the 92 patients with JMML. TFS was defined as the probability of being alive and transplantation free. Both death and transplantation were considered events. The probability of 5-year TFS in the aberrant methylation score (AMS) 0 cohort (solid line) was significantly higher than that in the AMS 1–2 (long dashed line) and AMS 3–4 cohorts (dashed line), p < 0.001. (B) Kaplan–Meier curves represent the probability of overall survival (OS) in the 92 patients with JMML. Death was considered an event. The probability of OS in both the AMS 0 (solid line) and 1–2 cohorts (long dashed line) was significantly higher than that in the AMS 3–4 cohort (dashed line), p < 0.001.
Mentions: The patients were classified into three cohorts according to the AMS score (Table 1 and Fig 3). The AMS 0 cohort displayed better survival without HSCT; specifically, the probabilities of 5-year TFS and OS in this cohort were 69% (95% CI, 45%–84%) and 76% (95% CI, 45%–91%), respectively. Patients in the AMS 1–2 cohort were rescued by HSCT. The probabilities of 5-year TFS and OS in this cohort were 6% (95% CI, 1%–17%) and 68% (95% CI, 50%–81%), respectively. In sharp contrast, the prognosis of patients in the AMS 3–4 cohort was not improved by HSCT, as the probabilities of 5-year TFS and OS in this cohort were 0% and 8% (95% CI, 0%–29%), respectively. Indeed, six of seven patients who received allogeneic HSCT in the AMS 3–4 cohort died during observation. Their causes of death consisted of progressive disease (n = 3), veno-occlusive disease (n = 2), and respiratory distress (n = 1), as shown in Table 2.

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