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

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

doi:10.18632/oncotarget.3644

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.

Highlights

In multiple myeloma (MM), malignant plasma cells accrue in the bone marrow (BM) expressing CD138, a marker of terminal B-cell differentiation
In the presence of cognate T-cell help, a distinctive phase of differentiation is initiated in the germinal center (GC), in secondary follicles of lymphoid organs that leads to the mainstay of memory, generating memory B-cells or long-lived plasma cells (LLPCs) located in the BM [2, 3]
On-going somatic hypermutation (SHM) occurs in B-cells during extensive proliferation within the dark zone (DZ) of a GC, whereas in the light zone (LZ) key selection events dictate B-cell fate [1, 4, 5]

Summary

Introduction

In multiple myeloma (MM), malignant plasma cells accrue in the bone marrow (BM) expressing CD138, a marker of terminal B-cell differentiation. Comparable observations were reported in a study of normal BM PCs from a single donor by deep sequencing, with the largest IGHV3-7 derived clonal expansion providing evidence of ICV to a level comparable to that seen in our data on normal PCs [24].

Results

Conclusion