Massive parallel IGHV gene sequencing reveals a germinal center pathway in origins of human multiple myeloma
Massive parallel IGHV gene sequencing reveals a germinal center pathway in origins of human multiple myeloma
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.
IGHV genes, germinal center, multiple myeloma, pathogenesis
13229-40
Cowan, Graeme
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Weston-Bell, Nicola J.
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Bryant, Dean
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Seckinger, Anja
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Hose, Dirk
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Zojer, Niklas
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Sahota, Surinder S.
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10 April 2015
Cowan, Graeme
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Weston-Bell, Nicola J.
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Bryant, Dean
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Seckinger, Anja
b734174c-f5be-4ac1-a250-30815ff1029c
Hose, Dirk
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Zojer, Niklas
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Sahota, Surinder S.
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Cowan, Graeme, Weston-Bell, Nicola J., Bryant, Dean, Seckinger, Anja, Hose, Dirk, Zojer, Niklas and Sahota, Surinder S.
(2015)
Massive parallel IGHV gene sequencing reveals a germinal center pathway in origins of human multiple myeloma.
Oncotarget, 6 (15), .
(doi:10.18632/oncotarget.3644).
(PMID:25929340)
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.
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IGHV gene GC origins MM 2015.pdf
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Accepted/In Press date: 24 March 2015
e-pub ahead of print date: 10 April 2015
Published date: 10 April 2015
Keywords:
IGHV genes, germinal center, multiple myeloma, pathogenesis
Organisations:
Cancer Sciences
Identifiers
Local EPrints ID: 376769
URI: http://eprints.soton.ac.uk/id/eprint/376769
ISSN: 1949-2553
PURE UUID: e1d16b31-7a09-4aca-8497-ed2de2890976
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Date deposited: 12 May 2015 11:04
Last modified: 15 Mar 2024 03:50
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Contributors
Author:
Graeme Cowan
Author:
Nicola J. Weston-Bell
Author:
Dean Bryant
Author:
Anja Seckinger
Author:
Dirk Hose
Author:
Niklas Zojer
Author:
Surinder S. Sahota
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