Massive parallel IGHV gene sequencing reveals a germinal center pathway in origins of human multiple myeloma

Graeme Cowan, Nicola J Weston-Bell, Dean Bryant, Anja Seckinger, Dirk Hose, Niklas Zojer, Surinder S Sahota

Research output: Contribution to journalArticlepeer-review

Abstract

Human multiple myeloma (MM) is characterized by accumulation of malignant terminally differentiated plasma cells (PCs) in the bone marrow (BM), raising the question when during maturation neoplastic transformation begins. Immunoglobulin IGHV genes carry imprints of clonal tumor history, delineating somatic hypermutation (SHM) events that generally occur in the germinal center (GC). Here, we examine MM-derived IGHV genes using massive parallel deep sequencing, comparing them with profiles in normal BM PCs. In 4/4 presentation IgG MM, monoclonal tumor-derived IGHV sequences revealed significant evidence for intraclonal variation (ICV) in mutation patterns. IGHV sequences of 2/2 normal PC IgG populations revealed dominant oligoclonal expansions, each expansion also displaying mutational ICV. Clonal expansions in MM and in normal BM PCs reveal common IGHV features. In such MM, the data fit a model of tumor origins in which neoplastic transformation is initiated in a GC B-cell committed to terminal differentiation but still targeted by on-going SHM. Strikingly, the data parallel IGHV clonal sequences in some monoclonal gammopathy of undetermined significance (MGUS) known to display on-going SHM imprints. Since MGUS generally precedes MM, these data suggest origins of MGUS and MM with IGHV gene mutational ICV from the same GC B-cell, arising via a distinctive pathway.

Original languageEnglish
Pages (from-to)13229-40
Number of pages12
JournalOncotarget
Volume6
Issue number15
DOIs
Publication statusPublished - 10 Apr 2015

Keywords

  • Bone Marrow Cells
  • Genes, Immunoglobulin
  • Germinal Center
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Immunoglobulin Heavy Chains
  • Immunoglobulin Variable Region
  • Monoclonal Gammopathy of Undetermined Significance
  • Multiple Myeloma
  • Mutation
  • Plasma Cells
  • Somatic Hypermutation, Immunoglobulin
  • Journal Article
  • Research Support, Non-U.S. Gov't

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