Promoter hypermethylation in MLL-r infant acute lymphoblastic leukemia: Biology and therapeutic targeting

Eric Schafer, Rafael Irizarry, Sandeep Negi, Emily McIntyre, Donald Small, Maria E. Figueroa, Ari Melnick, Patrick Brown

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70 Scopus citations

Abstract

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 analysisshowed 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.

Original languageEnglish (US)
Pages (from-to)4798-4809
Number of pages12
JournalBlood
Volume115
Issue number23
DOIs
StatePublished - Jun 10 2010

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Schafer, E., Irizarry, R., Negi, S., McIntyre, E., Small, D., Figueroa, M. E., Melnick, A., & Brown, P. (2010). Promoter hypermethylation in MLL-r infant acute lymphoblastic leukemia: Biology and therapeutic targeting. Blood, 115(23), 4798-4809. https://doi.org/10.1182/blood-2009-09-243634