The Genomic Landscape of Mantle Cell Lymphoma Is Related to the Epigenetically Determined Chromatin State of Normal B Cells

Blood. 2014 May 8;123(19):2988-96. doi: 10.1182/blood-2013-07-517177. Epub 2014 Mar 28.

Abstract

In this study, we define the genetic landscape of mantle cell lymphoma (MCL) through exome sequencing of 56 cases of MCL. We identified recurrent mutations in ATM, CCND1, MLL2, and TP53. We further identified a number of novel genes recurrently mutated in patients with MCL including RB1, WHSC1, POT1, and SMARCA4. We noted that MCLs have a distinct mutational profile compared with lymphomas from other B-cell stages. The ENCODE project has defined the chromatin structure of many cell types. However, a similar characterization of primary human mature B cells has been lacking. We defined, for the first time, the chromatin structure of primary human naïve, germinal center, and memory B cells through chromatin immunoprecipitation and sequencing for H3K4me1, H3K4me3, H3Ac, H3K36me3, H3K27me3, and PolII. We found that somatic mutations that occur more frequently in either MCLs or Burkitt lymphomas were associated with open chromatin in their respective B cells of origin, naïve B cells, and germinal center B cells. Our work thus elucidates the landscape of gene-coding mutations in MCL and the critical interplay between epigenetic alterations associated with B-cell differentiation and the acquisition of somatic mutations in cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins / genetics
  • B-Lymphocytes / metabolism*
  • Burkitt Lymphoma / genetics
  • Burkitt Lymphoma / pathology
  • Chromatin / genetics*
  • Chromatin / metabolism
  • Cyclin D1 / genetics
  • DNA Helicases / genetics
  • DNA-Binding Proteins / genetics
  • Epigenesis, Genetic
  • Exome / genetics
  • Gene Regulatory Networks
  • Genomics*
  • Germinal Center / metabolism
  • Germinal Center / pathology
  • Histone-Lysine N-Methyltransferase / genetics
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Lymphoma, Mantle-Cell / genetics*
  • Lymphoma, Mantle-Cell / pathology
  • Methylation
  • Mutation*
  • Neoplasm Proteins / genetics
  • Nuclear Proteins / genetics
  • Repressor Proteins / genetics
  • Retinoblastoma Protein / genetics
  • Sequence Analysis, DNA
  • Telomere-Binding Proteins / genetics
  • Transcription Factors / genetics
  • Tumor Suppressor Protein p53 / genetics

Substances

  • Chromatin
  • DNA-Binding Proteins
  • Histones
  • KMT2D protein, human
  • Neoplasm Proteins
  • Nuclear Proteins
  • POT1 protein, human
  • Repressor Proteins
  • Retinoblastoma Protein
  • Telomere-Binding Proteins
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Cyclin D1
  • Histone-Lysine N-Methyltransferase
  • NSD2 protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • SMARCA4 protein, human
  • DNA Helicases