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

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

Research output: Contribution to journalArticle

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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
Externally publishedYes

Fingerprint

Methylation
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Polymerase chain reaction
Genes
decitabine
Methyltransferases
Polymerase Chain Reaction
Assays
Cells
Cell Line
CpG Islands
DNA
Transcription
Therapeutics
Cytotoxicity
Reverse Transcription
Ligation
Cluster Analysis
Leukemia
Genome

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Promoter hypermethylation in MLL-r infant acute lymphoblastic leukemia : Biology and therapeutic targeting. / Schafer, Eric; Irizarry, Rafael; Negi, Sandeep; McIntyre, Emily; Small, Donald; Figueroa, Maria; Melnick, Ari; Brown, Patrick.

In: Blood, Vol. 115, No. 23, 10.06.2010, p. 4798-4809.

Research output: Contribution to journalArticle

Schafer, E, Irizarry, R, Negi, S, McIntyre, E, Small, D, Figueroa, M, Melnick, A & Brown, P 2010, 'Promoter hypermethylation in MLL-r infant acute lymphoblastic leukemia: Biology and therapeutic targeting', Blood, vol. 115, no. 23, pp. 4798-4809. https://doi.org/10.1182/blood-2009-09-243634
Schafer, Eric ; Irizarry, Rafael ; Negi, Sandeep ; McIntyre, Emily ; Small, Donald ; Figueroa, Maria ; Melnick, Ari ; Brown, Patrick. / Promoter hypermethylation in MLL-r infant acute lymphoblastic leukemia : Biology and therapeutic targeting. In: Blood. 2010 ; Vol. 115, No. 23. pp. 4798-4809.
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