Hypermethylation status and clinical outcome in patients with juvenile myelomonocytic leukemia (JMML).

<p>(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.</p

Profile of genetic mutations and aberrant methylation.

<p>(A) Mutation status of RAS pathway genes and secondary genes (<i>SETBP1</i> and <i>JAK3</i>) identified as gene targets. Aberrant methylation scores (AMS) in a cohort of 92 patients with juvenile myelomonocytic leukemia are summarized. A rhombus denotes a patient with Noonan syndrome-associated myeloproliferative disorder. (B) Mutations in <i>SETBP1</i> and <i>JAK3</i> were associated with a higher AMS. The mean AMS of patients with <i>SETBP1</i> and/or <i>JAK3</i> mutations was higher than that of patients without secondary mutations (p = 0.03).</p

Summary of DNA methylation in candidate genes.

<p>(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 <i>BMP4</i>, <i>CALCA</i>, <i>CDKN2A</i>, <i>CDKN2B</i>, <i>H19</i>, and <i>RARB</i>.</p

Patient characteristics.

<p>Patient characteristics.</p

Multivariate model for transplantation-free and overall survival.

<p>Multivariate model for transplantation-free and overall survival.</p