Genome-wide epigenetic analysis delineates a biologically distinct immature acute leukemia with myeloid/T-lymphoid features.
Acute myeloid leukemia is a heterogeneous disease from the molecular and biologic standpoints, and even patients with a specific gene expression profile may present clinical and molecular heterogeneity. We studied the epigenetic profiles of a cohort of patients who shared a common gene expression profile but differed in that only half of them harbored mutations of the CEBPA locus, whereas the rest presented with silencing of this gene and coexpression of certain T-cell markers. DNA methylation studies revealed that these 2 groups of patients could be readily segregated in an unsupervised fashion based on their DNA methylation profiles alone. Furthermore, CEBPA silencing was associated with the presence of an aberrant DNA hypermethylation signature, which was not present in the CEBPA mutant group. This aberrant hypermethylation occurred more frequently at sites within CpG islands. CEBPA-silenced leukemias also displayed marked hypermethylation compared with normal CD34(+) hematopoietic cells, whereas CEBPA mutant cases showed only mild changes in DNA methylation compared with these normal progenitors. Biologically, CEBPA-silenced leukemias presented with a decreased response to myeloid growth factors in vitro.
Figueroa
Maria E
ME
Department of Medicine (Hematology Oncology Division), Weill Cornell Medical College, New York, NY 10021, USA.
Wouters
Bas J
BJ
Skrabanek
Lucy
L
Glass
Jacob
J
Li
Yushan
Y
Erpelinck-Verschueren
Claudia A J
CA
Langerak
Anton W
AW
Löwenberg
Bob
B
Fazzari
Melissa
M
Greally
John M
JM
Valk
Peter J M
PJ
Melnick
Ari
A
Delwel
Ruud
R
D000293:Adolescent; D000328:Adult; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics*; D015331:Cohort Studies; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000737:chemistry* / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D053263:Gene Regulatory Networks; D020868:Gene Silencing; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000145:classification / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000145:classification / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; D004273:DNA, Neoplasm; D007377:Interleukin-3; D009363:Neoplasm Proteins; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor