TY - JOUR
T1 - Genomewide DNA methylation analysis reveals novel targets for drug development in mantle cell lymphoma
AU - Leshchenko, Violetta V.
AU - Kuo, Pei Yu
AU - Shaknovich, Rita
AU - Yang, David T.
AU - Gellen, Tobias
AU - Petrich, Adam
AU - Yu, Yiting
AU - Remache, Yvonne
AU - Weniger, Marc A.
AU - Rafiq, Sarwish
AU - Suh, K. Stephen
AU - Goy, Andre
AU - Wilson, Wyndham
AU - Verma, Amit
AU - Braunschweig, Ira
AU - Muthusamy, Natarajan
AU - Kahl, Brad S.
AU - Byrd, John C.
AU - Wiestner, Adrian
AU - Melnick, Ari
AU - Parekh, Samir
PY - 2010/8/19
Y1 - 2010/8/19
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2009-12-257485
DO - 10.1182/blood-2009-12-257485
M3 - Review article
C2 - 20427703
AN - SCOPUS:77956525903
SN - 0006-4971
VL - 116
SP - 1025
EP - 1034
JO - Blood
JF - Blood
IS - 7
ER -