Genomewide DNA methylation analysis reveals novel targets for drug development in mantle cell lymphoma.
Mantle cell lymphoma (MCL) is a mostly incurable malignancy arising from naive B cells (NBCs) in the mantle zone of lymph nodes. We analyzed genomewide methylation in MCL patients with the HELP (HpaII tiny fragment Enrichment by Ligation-mediated PCR) assay and found significant aberrancy in promoter methylation patterns compared with normal NBCs. Using biologic and statistical criteria, we further identified 4 hypermethylated genes CDKN2B, MLF-1, PCDH8, and HOXD8 and 4 hypomethylated genes CD37, HDAC1, NOTCH1, and CDK5 when aberrant methylation was associated with inverse changes in mRNA levels. Immunohistochemical analysis of an independent cohort of MCL patient samples confirmed CD37 surface expression in 93% of patients, validating its selection as a target for MCL therapy. Treatment of MCL cell lines with a small modular immunopharmaceutical (CD37-SMIP) resulted in significant loss of viability in cell lines with intense surface CD37 expression. Treatment of MCL cell lines with the DNA methyltransferase inhibitor decitabine resulted in reversal of aberrant hypermethylation and synergized with the histone deacetylase inhibitor suberoylanilide hydroxamic acid in induction of the hypermethylated genes and anti-MCL cytotoxicity. Our data show prominent and aberrant promoter methylation in MCL and suggest that differentially methylated genes can be targeted for therapeutic benefit in MCL.
Leshchenko
Violetta V
VV
Albert Einstein Cancer Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Kuo
Pei-Yu
PY
Shaknovich
Rita
R
Yang
David T
DT
Gellen
Tobias
T
Petrich
Adam
A
Yu
Yiting
Y
Remache
Yvonne
Y
Weniger
Marc A
MA
Rafiq
Sarwish
S
Suh
K Stephen
KS
Goy
Andre
A
Wilson
Wyndham
W
Verma
Amit
A
Braunschweig
Ira
I
Muthusamy
Natarajan
N
Kahl
Brad S
BS
Byrd
John C
JC
Wiestner
Adrian
A
Melnick
Ari
A
Parekh
Samir
S
D015703:Antigens, CD / Q000235:genetics; D000951:Antigens, Neoplasm / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D019175:DNA Methylation; D015195:Drug Design; D055808:Drug Discovery; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D015894:Genome, Human; D006801:Humans; D007124:Immunoenzyme Techniques; D020522:Lymphoma, Mantle-Cell / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D059470:Tetraspanins
D015703:Antigens, CD; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; C059071:CD37 protein, human; D059470:Tetraspanins