Promoter hypermethylation in MLL-r infant acute lymphoblastic leukemia: biology and therapeutic targeting.
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.
Schafer
Eric
E
Department of Oncology, Johns Hopkins University, Baltimore, MD, USA.
Irizarry
Rafael
R
Negi
Sandeep
S
McIntyre
Emily
E
Small
Donald
D
Figueroa
Maria E
ME
Melnick
Ari
A
Brown
Patrick
P
D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D018899:CpG Islands; D019175:DNA Methylation / Q000187:drug effects* / Q000235:genetics; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D015321:Gene Rearrangement / Q000187:drug effects / Q000235:genetics; D020868:Gene Silencing / Q000187:drug effects; D055106:Genome-Wide Association Study; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007223:Infant; D008297:Male; D051788:Myeloid-Lymphoid Leukemia Protein / Q000096:biosynthesis* / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D011401:Promoter Regions, Genetic
D004791:Enzyme Inhibitors; C497422:KMT2A protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D000077209:Decitabine; D015254:DNA Modification Methylases; D011495:Histone-Lysine N-Methyltransferase; D001374:Azacitidine