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Cell Cycle Reprogramming for PI3K Inhibition Overrides Relapse-Specific C481S BTK Mutation Revealed by Longitudinal Functional Genomics in Mantle Cell Lymphoma

ABSTRACT: The RNA-seq data presented in this study include libraries from Mantle Cell Lymphoma (MCL) tumor cells sequentially obtained from patients

ORGANISM(S): Homo sapiens

PROVIDER: GSE55405 | GEO | 2017/02/25

SECONDARY ACCESSION(S): PRJNA239521

REPOSITORIES: GEO

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Project description:Mantle Cell Lymphoma (MCL) is a mostly incurable malignancy arising from naïve B cells (NBC) in the mantle zone of lymph node follicles. We analyzed genome-wide methylation in MCL patients using the HELP (Hpa II tiny fragment Enrichment by Ligation mediated PCR) assay and found significant aberrancy in promoter methylation patterns as compared to normal NBCs. Using biological and stringent statistical criteria, we further identified four hypermethylated genes CDKN2B, MLF-1, PCDH8, HOXD8 and four hypomethylated genes CD37, HDAC1, NOTCH1 and CDK5 where aberrant methylation was associated with inverse changes in mRNA levels. MassArray Epityper analysis confirmed the presence of differential methylation at the promoter region of these genes. Immunohistochemical analysis of an independent cohort of 14 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 novel 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 HDAC inhibitor SAHA in induction of the four hypermethylated genes CDKN2B, MLF-1, PCDH8 and HOXD8. The combination of Decitabine and SAHA also resulted in potent and synergistic anti-MCL cytotoxicity as compared to either drug alone. In conclusion, our analysis shows prominent and aberrant methylation of the MCL genome and identifies novel differentially methylated and expressed genes in MCL cell lines and patient samples. Furthermore, our data suggest that differentially methylated genes can be targeted for therapeutic benefit in MCL. Gene expression profiling by array comprised of 8 mantle cell lymphoma (MCL) cell lines and 8 leukemic blast from blood from patients newly diagnosed with MCL. Unbiased genome-wide analysis of DNA methylation in leukemic blast from peripheral blood or pheresis products from 22 patients newly diagnosed with mantle cell lymphoma (MCL) prior to any treatment. 10 IgD+ Na ve B cells from specimens from healthy donors undergoing routine tonsillectomy were used as appropriate controls. Methylation patterns of 13 MCL cell lines were also compared.

Dataset Information

Cell Cycle Reprogramming for PI3K Inhibition Overrides Relapse-Specific C481S BTK Mutation Revealed by Longitudinal Functional Genomics in Mantle Cell Lymphoma

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