Myeloma is characterized by stage-specific alterations in DNA methylation that occur early during myelomagenesis

Christoph J. Heuck, Jayesh Mehta, Tushar Bhagat, Krishna Gundabolu, Yiting Yu, Shahper Khan, Grigoris Chrysofakis, Carolina Schinke, Joseph Tariman, Eric Vickrey, Natalie Pulliam, Sangeeta Nischal, Li Zhou, Sanchari Bhattacharyya, Richard Meagher, Caroline Hu, Shahina Maqbool, Masako Suzuki, Samir Parekh, Frederic ReuUlrich Steidl, John Greally, Amit Verma, Seema B. Singhal

Research output: Contribution to journalArticle

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Abstract

Epigenetic changes play important roles in carcinogenesis and influence initial steps in neoplastic transformation by altering genome stability and regulating gene expression. To characterize epigenomic changes during the transformation of normal plasma cells to myeloma, we modified the HpaII tiny fragment enrichment by ligation-mediated PCR assay to work with small numbers of purified primary marrow plasma cells. The nano-HpaII tiny fragment enrichment by ligation-mediated PCR assay was used to analyze the methylome of CD138+ cells from 56 subjects representing premalignant (monoclonal gammopathy of uncertain significance), early, and advanced stages of myeloma, as well as healthy controls. Plasma cells from premalignant and early stages of myeloma were characterized by striking, widespread hypomethylation. Gene-specific hypermethylation was seen to occur in the advanced stages, and cell lines representative of relapsed cases were found to be sensitive to decitabine. Aberrant demethylation in monoclonal gammopathy of uncertain significance occurred primarily in CpG islands, whereas differentially methylated loci in cases of myeloma occurred predominantly outside of CpG islands and affected distinct sets of gene pathways, demonstrating qualitative epigenetic differences between premalignant and malignant stages. Examination of the methylation machinery revealed that the methyltransferase, DNMT3A, was aberrantly hypermethylated and underexpressed, but not mutated in myeloma. DNMT3A underexpression was also associated with adverse overall survival in a large cohort of patients, providing insights into genesis of hypomethylation in myeloma. These results demonstrate widespread, stage-specific epigenetic changes during myelomagenesis and suggest that early demethylation can be a potential contributor to genome instability seen in myeloma. We also identify DNMT3A expression as a novel prognostic biomarker and suggest that relapsed cases can be therapeutically targeted by hypomethylating agents.

Original languageEnglish (US)
Pages (from-to)2966-2975
Number of pages10
JournalJournal of Immunology
Volume190
Issue number6
DOIs
StatePublished - Mar 15 2013

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DNA Methylation
Epigenomics
Paraproteinemias
CpG Islands
Genomic Instability
decitabine
Plasma Cells
Ligation
Polymerase Chain Reaction
Methyltransferases
Multiple Myeloma
Methylation
Genes
Carcinogenesis
Biomarkers
Bone Marrow
Gene Expression
Cell Line
Survival

ASJC Scopus subject areas

  • Immunology

Cite this

Myeloma is characterized by stage-specific alterations in DNA methylation that occur early during myelomagenesis. / Heuck, Christoph J.; Mehta, Jayesh; Bhagat, Tushar; Gundabolu, Krishna; Yu, Yiting; Khan, Shahper; Chrysofakis, Grigoris; Schinke, Carolina; Tariman, Joseph; Vickrey, Eric; Pulliam, Natalie; Nischal, Sangeeta; Zhou, Li; Bhattacharyya, Sanchari; Meagher, Richard; Hu, Caroline; Maqbool, Shahina; Suzuki, Masako; Parekh, Samir; Reu, Frederic; Steidl, Ulrich; Greally, John; Verma, Amit; Singhal, Seema B.

In: Journal of Immunology, Vol. 190, No. 6, 15.03.2013, p. 2966-2975.

Research output: Contribution to journalArticle

Heuck, CJ, Mehta, J, Bhagat, T, Gundabolu, K, Yu, Y, Khan, S, Chrysofakis, G, Schinke, C, Tariman, J, Vickrey, E, Pulliam, N, Nischal, S, Zhou, L, Bhattacharyya, S, Meagher, R, Hu, C, Maqbool, S, Suzuki, M, Parekh, S, Reu, F, Steidl, U, Greally, J, Verma, A & Singhal, SB 2013, 'Myeloma is characterized by stage-specific alterations in DNA methylation that occur early during myelomagenesis', Journal of Immunology, vol. 190, no. 6, pp. 2966-2975. https://doi.org/10.4049/jimmunol.1202493
Heuck, Christoph J. ; Mehta, Jayesh ; Bhagat, Tushar ; Gundabolu, Krishna ; Yu, Yiting ; Khan, Shahper ; Chrysofakis, Grigoris ; Schinke, Carolina ; Tariman, Joseph ; Vickrey, Eric ; Pulliam, Natalie ; Nischal, Sangeeta ; Zhou, Li ; Bhattacharyya, Sanchari ; Meagher, Richard ; Hu, Caroline ; Maqbool, Shahina ; Suzuki, Masako ; Parekh, Samir ; Reu, Frederic ; Steidl, Ulrich ; Greally, John ; Verma, Amit ; Singhal, Seema B. / Myeloma is characterized by stage-specific alterations in DNA methylation that occur early during myelomagenesis. In: Journal of Immunology. 2013 ; Vol. 190, No. 6. pp. 2966-2975.
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AU - Yu, Yiting

AU - Khan, Shahper

AU - Chrysofakis, Grigoris

AU - Schinke, Carolina

AU - Tariman, Joseph

AU - Vickrey, Eric

AU - Pulliam, Natalie

AU - Nischal, Sangeeta

AU - Zhou, Li

AU - Bhattacharyya, Sanchari

AU - Meagher, Richard

AU - Hu, Caroline

AU - Maqbool, Shahina

AU - Suzuki, Masako

AU - Parekh, Samir

AU - Reu, Frederic

AU - Steidl, Ulrich

AU - Greally, John

AU - Verma, Amit

AU - Singhal, Seema B.

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N2 - Epigenetic changes play important roles in carcinogenesis and influence initial steps in neoplastic transformation by altering genome stability and regulating gene expression. To characterize epigenomic changes during the transformation of normal plasma cells to myeloma, we modified the HpaII tiny fragment enrichment by ligation-mediated PCR assay to work with small numbers of purified primary marrow plasma cells. The nano-HpaII tiny fragment enrichment by ligation-mediated PCR assay was used to analyze the methylome of CD138+ cells from 56 subjects representing premalignant (monoclonal gammopathy of uncertain significance), early, and advanced stages of myeloma, as well as healthy controls. Plasma cells from premalignant and early stages of myeloma were characterized by striking, widespread hypomethylation. Gene-specific hypermethylation was seen to occur in the advanced stages, and cell lines representative of relapsed cases were found to be sensitive to decitabine. Aberrant demethylation in monoclonal gammopathy of uncertain significance occurred primarily in CpG islands, whereas differentially methylated loci in cases of myeloma occurred predominantly outside of CpG islands and affected distinct sets of gene pathways, demonstrating qualitative epigenetic differences between premalignant and malignant stages. Examination of the methylation machinery revealed that the methyltransferase, DNMT3A, was aberrantly hypermethylated and underexpressed, but not mutated in myeloma. DNMT3A underexpression was also associated with adverse overall survival in a large cohort of patients, providing insights into genesis of hypomethylation in myeloma. These results demonstrate widespread, stage-specific epigenetic changes during myelomagenesis and suggest that early demethylation can be a potential contributor to genome instability seen in myeloma. We also identify DNMT3A expression as a novel prognostic biomarker and suggest that relapsed cases can be therapeutically targeted by hypomethylating agents.

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