A CpG island methylator phenotype in acute myeloid leukemia independent of IDH mutations and associated with a favorable outcome

• Published in: Leukemia Vol. 31; no. 10; pp. 2011 - 2019
• Main Authors: Kelly, A D, Kroeger, H, Yamazaki, J, Taby, R, Neumann, F, Yu, S, Lee, J T, Patel, B, Li, Y, He, R, Liang, S, Lu, Y, Cesaroni, M, Pierce, S A, Kornblau, S M, Bueso-Ramos, C E, Ravandi, F, Kantarjian, H M, Jelinek, J, Issa, J-PJ
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-10-2017; Nature Publishing Group
• Subjects: 45/23; 45/61; 45/91; 631/67/69; Acute myelocytic leukemia; Acute myeloid leukemia; Adolescent; Adult; Aged; Cancer; Cancer Research; Care and treatment; CpG Islands; Critical Care Medicine; Data processing; Datasets; Datasets as Topic; Development and progression; DNA Methylation; DNA, Neoplasm - genetics; Epigenetics; Female; Gene expression; Gene mutation; Genetic aspects; Genomes; Genotype & phenotype; Health aspects; Hematology; Humans; Intensive; Internal Medicine; Isocitrate Dehydrogenase - genetics; Leukemia; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - mortality; Male; Medicine; Medicine & Public Health; Methylation; Middle Aged; Mutation; Myeloid leukemia; Oncology; original-article; Oxidoreductases; Phenotype; Phenotypes; Pilot Projects; Pluripotency; Prognosis; Regulators; Retrospective Studies; Risk; Survival Analysis; Young Adult
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2017.12

Genetic changes are infrequent in acute myeloid leukemia (AML) compared with other malignancies and often involve epigenetic regulators, suggesting that an altered epigenome may underlie AML biology and outcomes. In 96 AML cases including 65 pilot samples selected for cured/not-cured, we found higher CpG island (CGI) promoter methylation in cured patients. Expanded genome-wide digital restriction enzyme analysis of methylation data revealed a CGI methylator phenotype independent of
IDH1/2
mutations we term AML-CGI methylator phenotype (CIMP) (A-CIMP
+
). A-CIMP was associated with longer overall survival (OS) in this data set (median OS, years: A-CIMP
+
=not reached, CIMP
-
=1.17;
P
=0.08). For validation we used 194 samples from The Cancer Genome Atlas interrogated with Illumina 450k methylation arrays where we confirmed longer OS in A-CIMP (median OS, years: A-CIMP
+
=2.34, A-CIMP
-
=1.00;
P
=0.01). Hypermethylation in A-CIMP
+
favored CGIs (OR: CGI/non-CGI=5.21), and while A-CIMP
+
was enriched in
CEBPA
(
P
=0.002) and
WT1
mutations (
P
=0.02), 70% of cases lacked either mutation. Hypermethylated genes in A-CIMP
+
function in pluripotency maintenance, and a gene expression signature of A-CIMP was associated with outcomes in multiple data sets. We conclude that CIMP in AML cannot be explained solely by gene mutations (for example,
IDH1/2
,
TET2
), and that curability in A-CIMP
+
AML should be validated prospectively.