TitlePromoter hypermethylation in MLL-r infant acute lymphoblastic leukemia: biology and therapeutic targeting.
Publication TypeJournal Article
Year of Publication2010
AuthorsSchafer, Eric, Irizarry Rafael, Negi Sandeep, McIntyre Emily, Small Donald, Figueroa Maria E., Melnick Ari, and Brown Patrick
Date Published2010 Jun 10
KeywordsAzacitidine, Cell Line, Tumor, Child, Child, Preschool, Cohort Studies, CpG Islands, Decitabine, DNA Methylation, DNA Modification Methylases, Enzyme Inhibitors, Female, Gene Rearrangement, Gene Silencing, Genome-Wide Association Study, Histone-Lysine N-Methyltransferase, Humans, Infant, Male, Myeloid-Lymphoid Leukemia Protein, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Promoter Regions, Genetic

<p>Cooperating leukemogenic events in MLL-rearranged (MLL-r) infant acute lymphoblastic leukemia (ALL) are largely unknown. We explored the role of promoter CpG island hypermethylation in the biology and therapeutic targeting of MLL-r infant ALL. The HELP (HpaII tiny fragment enrichment by ligation-mediated polymerase chain reaction [PCR]) assay was used to examine genome-wide methylation of a cohort of MLL-r infant leukemia samples (n = 5), other common childhood ALLs (n = 5), and normals (n = 5). Unsupervised analysis showed tight clustering of samples into their known biologic groups, indicating large differences in methylation patterns. Global hypermethylation was seen in the MLL-r cohort compared with both the normals and the others, with ratios of significantly (P < .001) hypermethylated to hypomethylated CpGs of 1.7 and 2.9, respectively. A subset of 7 differentially hypermethylated genes was assayed by quantitative reverse-transcription (qRT)-PCR, confirming relative silencing in 5 of 7. In cell line treatment assays with the DNA methyltransferase inhibitor (DNMTi) decitabine, MLL-r (but not MLL wild-type cell lines) showed dose- and time-dependent cytotoxicity and re-expression of 4 of the 5 silenced genes. Methylation-specific PCR (MSP) confirmed promoter hypermethylation at baseline, and a relative decrease in methylation after treatment. DNMTi may represent a novel molecularly targeted therapy for MLL-r infant ALL.</p>

Alternate JournalBlood
PubMed ID20215641
PubMed Central IDPMC2890186
Grant ListR01 CA090668 / CA / NCI NIH HHS / United States
T32 CA060441 / CA / NCI NIH HHS / United States
R01 GM083084 / GM / NIGMS NIH HHS / United States
K23 CA111728 / CA / NCI NIH HHS / United States
R01 GM083084-03 / GM / NIGMS NIH HHS / United States