Specific promoter methylation identifies different subgroups of MLL-rearranged infant acute lymphoblastic leukemia, influences clinical outcome, and provides therapeutic options.
MLL-rearranged infant acute lymphoblastic leukemia (ALL) remains the most aggressive type of childhood leukemia, displaying a unique gene expression profile. Here we hypothesized that this characteristic gene expression signature may have been established by potentially reversible epigenetic modifications. To test this hypothesis, we used differential methylation hybridization to explore the DNA methylation patterns underlying MLL-rearranged ALL in infants. The obtained results were correlated with gene expression data to confirm gene silencing as a result of promoter hypermethylation. Distinct promoter CpG island methylation patterns separated different genetic subtypes of MLL-rearranged ALL in infants. MLL translocations t(4;11) and t(11;19) characterized extensively hypermethylated leukemias, whereas t(9;11)-positive infant ALL and infant ALL carrying wild-type MLL genes epigenetically resembled normal bone marrow. Furthermore, the degree of promoter hypermethylation among infant ALL patients carrying t(4;11) or t(11;19) appeared to influence relapse-free survival, with patients displaying accentuated methylation being at high relapse risk. Finally, we show that the demethylating agent zebularine reverses aberrant DNA methylation and effectively induces apoptosis in MLL-rearranged ALL cells. Collectively these data suggest that aberrant DNA methylation occurs in the majority of MLL-rearranged infant ALL cases and guides clinical outcome. Therefore, inhibition of aberrant DNA methylation may be an important novel therapeutic strategy for MLL-rearranged ALL in infants.
Department of Pediatric Oncology/Hematology, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.
Dominique J P M
DJ
Stumpel
Pauline
P
Schneider
Eddy H J
EH
van Roon
Judith M
JM
Boer
Paola
P
de Lorenzo
Maria G
MG
Valsecchi
Renee X
RX
de Menezes
Rob
R
Pieters
Ronald W
RW
Stam
D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D016000:Cluster Analysis; D018899:CpG Islands / Q000235:genetics; D003562:Cytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D019175:DNA Methylation; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007223:Infant; D019169:Jurkat Cells; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D016019:Survival Analysis; D014178:Translocation, Genetic; D016896:Treatment Outcome
D051788:Myeloid-Lymphoid Leukemia Protein; D003562:Cytidine; C009131:pyrimidin-2-one beta-ribofuranoside