Clonotypic IgM V/D/J sequence analysis in Waldenstrom macroglobulinemia suggests an unusual B-cell origin and an expansion of polyclonal B cells in peripheral blood

Kriangkum, Jitra; Taylor, Brian J.; Treon, Steven P.; Mant, Michael J.; Belch, Andrew R.; Pilarski, Linda M.

doi:10.1182/blood-2003-11-4024

Cited by 86 publications

(76 citation statements)

References 44 publications

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“…9,10 Ongoing mutational activity targeting IGHV in HCL is also a recurrent feature of leukemic cells, in which AID transcripts are constitutively expressed, 11 and may lead to the accrual of higher levels of mutations observed in this tumor. 4,11 IGHV-mutated CD27 Àve cells also comprise part of the tumor clone in Waldenstrom's macroglobulinemia, 6,7 but here it is unknown whether malignant cells derive from unusual IgM þ D þ CD27 Àve memory B cells that we describe herein or from conventional CD27 þ memory B cells that subsequently lose CD27 expression. If the latter, it will then also be relevant to know whether IgM þ D þ CD27 þ -mutated B cells are GC-or non-GC-derived in defining origins of Waldenstrom's macroglobulinemia.…”

Section: Discussionmentioning

confidence: 96%

“…4,5 In addition, in IgM-expressing Waldenstrom's macroglobulinemia, mutated tumor cells are seen in CD27 Àve fractions, 6,7 and it has been proposed that origins of this disease may be from 'unusual' memory B cells. 6 Interestingly, more recent observations indicate that the normal human B-cell memory pool may as yet not be mapped fully. These studies have examined the association of CD27 expression as an absolute requirement in normal human memory B cells.…”

Section: Introductionmentioning

confidence: 99%

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Defining origins of malignant B cells: a new circulating normal human IgM+D+ B-cell subset lacking CD27 expression and displaying somatically mutated IGHV genes as a relevant memory population

et al. 2009

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In probing the cell of origin in malignant B cells, an imprint of somatic hypermutation (SHM) in immunoglobulin (Ig) variable (V) region genes delineates antigen encounter, and identifying the precise pathway generating SHM in the normal B-cell counterpart becomes relevant. SHM remains the definitive memory imprint in normal human B cells, but CD27 expression also delineates memory. Recently, dye extrusion adenosine triphosphate-binding transporter assays identified circulating isotype-switched memory B cells that lacked CD27, yet exhibited low levels of SHM. To extend findings, we report a pre-switched CD27 Àve circulating memory B-cell population in normal blood using comparable assays, and isolated CD19 þ IgM þ D þ CD27 Àve cells (499% purity) for the analysis of IGHV5/IGHV3-IGHM transcripts. Of these (n ¼ 334), B78% were germ line and naive B cell derived. Strikingly, 21.9% of the transcripts were mutated. They showed 3-5 mutations (13.5% of sequences) and 45 mutations (8.4% of sequences) per transcript. Accrual of mutations in a subset of CD19 þ IgM þ D þ CD27 Àve cells define a new circulating pre-switched memory B-cell pool, present in substantial numbers in the population harboring naive B cells. These CD19 þ IgM þ D þ CD27 Àve memory B cells may have a distinct lineage and function, and seem relevant to understanding origins of malignant B cells, in particular those of hairy cell leukemia cells, which display mutated V genes yet lack CD27 expression.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Defining origins of malignant B cells: a new circulating normal human IgM+D+ B-cell subset lacking CD27 expression and displaying somatically mutated IGHV genes as a relevant memory population

et al. 2009

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“…Given that CD27 interacts with CD70 on activated T cells, it is believable that the absence of CD27 might impair the ability of these cells to receive the complete and persistent degree of T cell help required to complete a germinal center reaction (Toellner et al, 2002). Interestingly, somatic hypermutation in the absence of CD27 is present in two different B cell tumors as Waldenstrom's macroglobulinemia and hairy cell leukemia, for which an extragerminal center derivation has been proposed (Kriangkum et al, 2004;Forconi et al, 2004).…”

Section: Markers Of Memory B Lymphocytesmentioning

confidence: 99%

B cells and immunosenescence: A focus on IgG+IgD−CD27− (DN) B cells in aged humans

Bulati¹,

Buffa²,

Candore³

et al. 2011

Ageing Research Reviews

101

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a b s t r a c tImmunosenescence contributes to the decreased ability of the elderly to control infectious diseases, which is also reflected in their generally poor response to new antigens and vaccination. It is known that the T cell branch of the immune system is impaired in the elderly mainly due to expansion of memory/effector cells that renders the immune system less able to respond to new antigens. B lymphocytes are also impaired in the elderly in terms of their response to new antigens. In this paper we review recent work on B cell immunosenescence focusing our attention on memory B cells and a subset of memory B cells (namely IgG + IgD − CD27 − ) that we have demonstrated is increased in healthy elderly.

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“…Thus, in most cases, the neoplastic B cells present somatic hypermutation in the genes coding the hypervariable regions of the immunoglobulin heavy chains (V H genes). 11,12 However, in some cases, the neoplastic B-cells are derived from B-lymphocytes which have undergone somatic mutation outside of germinal centers. 13 In other cases, there is no evidence of somatic mutations in the V H genes, which may indicate that they are derived from pre-germinal center B--lymphocytes, such as "virgin" B-lymphocytes.…”

mentioning

confidence: 99%

“…13 In other cases, there is no evidence of somatic mutations in the V H genes, which may indicate that they are derived from pre-germinal center B--lymphocytes, such as "virgin" B-lymphocytes. 12 In relation to the mechanisms involved in the pathophysiology of WM, the blocking of immunoglobulin isotype switching and the role of cytokines is noteworthy.…”

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confidence: 99%

Waldenström's macroglobulinemia - a review

Coimbra

Neves

Lima

et al. 2014

Rev. Assoc. Med. Bras.

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Waldenström's macroglobulinemia (WM) is a lymphoproliferative disease of B lymphocytes, characterized by a lymphoplasmocytic lymphoma in the bone marrow and by IgM monoclonal hypergammaglobulinemia. It was first described in 1944 by Jan Gösta Waldenström, reporting two patients with oronasal bleeding, lymphadenopathy, anemia, thrombocytopenia, high erythrocyte sedimentation rate and serum viscosity, normal radiography and bone marrow infiltrated by lymphoid cells. The WM is a rare disease with a typically indolent clinical course, affecting mainly individuals aged between 63 and 68 years. Most patients have clinical signs and symptoms related to hyperviscosity resulting from IgM monoclonal gammopathy, and/or cytopenias resulting from bone marrow infiltration by lymphoma. The differential diagnosis with other lymphomas is essential for the assessment of prognosis and therapeutic approach. Treatment of patients with asymptomatic WM does not improve the quality of life of patients, or increase their survival, being recommended, therefore, their follow-up. For the treatment of symptomatic patients, alkylating agents, purine analogs and anti-CD20 monoclonal antibodies are used. However, the disease is incurable and the response to therapy is not always favorable. Recent studies have shown promising results with bortezomib, an inhibitor of proteasomes, and some patients respond to thalidomide. In patients with relapse or refractory to therapy, autologous transplantation may be indicated. The aim of this paper is to describe in detail the current knowledge on the pathophysiology of WM, main clinical manifestations, diagnosis, prognosis and treatment.

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Clonotypic IgM V/D/J sequence analysis in Waldenstrom macroglobulinemia suggests an unusual B-cell origin and an expansion of polyclonal B cells in peripheral blood

Abstract: Analysis of clonotypic immunoglobulin

Cited by 86 publications

References 44 publications

Defining origins of malignant B cells: a new circulating normal human IgM+D+ B-cell subset lacking CD27 expression and displaying somatically mutated IGHV genes as a relevant memory population

Defining origins of malignant B cells: a new circulating normal human IgM+D+ B-cell subset lacking CD27 expression and displaying somatically mutated IGHV genes as a relevant memory population

B cells and immunosenescence: A focus on IgG+IgD−CD27− (DN) B cells in aged humans

Waldenström's macroglobulinemia - a review

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