Homing of Human B Cells to Lymphoid Organs and B-Cell Lymphoma Engraftment Are Controlled by Cell Adhesion Molecule JAM-C

Abstract Rituximab, a monoclonal antibody that targets CD20 on B cells, is now central to the treatment of a variety of malignant and autoimmune disorders. Despite this success, a substantial proportion of B-cell lymphomas are unresponsive or develop resistance, hence more potent anti-CD20 monoclonal antibodies (mAbs) are continuously being sought. Here we demonstrate that type II (tositumomab-like) anti-CD20 mAbs are 5 times more potent than type I (rituximab-like) reagents in depleting human CD20 Tg B cells, despite both operating exclusively via activatory Fcγ receptor–expressing macrophages. Much of this disparity in performance is attributable to type I mAb-mediated internalization of CD20 by B cells, leading to reduced macrophage recruitment and the degradation of CD20/mAb complexes, shortening mAb half-life. Importantly, human B cells from healthy donors and most cases of chronic lymphatic leukemia and mantle cell lymphoma, showed rapid CD20 internalization that paralleled that seen in the Tg mouse B cells, whereas most follicular lymphoma and diffuse large B-cell lymphoma cells were far more resistant to CD20 loss. We postulate that differences in CD20 modulation may play a central role in determining the relative efficacy of rituximab in treating these diseases and strengthen the case for focusing on type II anti-CD20 mAb in the clinic.

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Ki-B5: a monoclonal antibody unrelated to CD45 recognizes normal and neoplastic human B cells in routine paraffin sections

Blood ◽

10.1182/blood.v77.4.809.bloodjournal774809 ◽

1991 ◽

Vol 77 (4) ◽

pp. 809-817 ◽

Cited By ~ 1

Author(s):

ML Hansmann ◽

HH Wacker ◽

J Gralla ◽

H Lumbeck ◽

M Kossmahl ◽

...

Keyword(s):

Monoclonal Antibody ◽

T Cell ◽

B Cells ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Protein Fractions ◽

Paraffin Sections ◽

Human B Cells ◽

Normal Human

In the search for immunoreagents appropriate for the histopathologic diagnosis of malignant B-cell lymphomas in routinely processed paraffin sections, a new monoclonal antibody, Ki-B5, was generated using a high- grade B-cell lymphoma as the immunogene. Ki-B5 is a mouse IgG1/kappa that recognizes five protein fractions of about 84, 82, 55, 48, and 27 Kd after biosynthetic radiolabeling and immunoprecipitation. Protein fractions with the molecular weights of approximately 84 and 82 Kd were expressed on the cell surface and show that Ki-B5 is probably unrelated to CD45. It was possible through electron microscopy to visualize the membrane-bound portion of Ki-B5. Extensive immunohistologic studies on normal human tissue and various neoplasias demonstrated the high specificity of Ki-B5 to normal human B cells and a minor subgroup of plasma cells. Except for ML-2, which is a myelomonocytic human cell line, Ki-B5 exclusively recognized the B-cell lineage, including EB-3, BALL-1, and NALM-1. All carcinomas, sarcomas, and malignant melanomas tested with Ki-B5 were negative. Although normal granulocytes and monocytes were constantly negative, three of eight myelomonocytic leukemias coreacted with this antibody. Eight of the 57 T-cell lymphomas studied were positive to Ki-B5. Five were classified as lymphoblastic, two represented T8-CLL, and one was classified as immunoblastic T-cell lymphoma. Only 3 of 126 cases of B-cell lymphoma, including rare types not considered in the current classifications, were negative to Ki-B5. Plasmacytomas were also negative, except for one case. Irrespective of the cases of lymphoblastic lymphoma and plasmacytoma, Ki-B5 represents a new monoclonal antibody appropriate for the diagnosis and immunophenotyping of malignant lymphomas in routinely processed paraffin sections.

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Constitutive alternative NF-κB signaling promotes marginal zone B-cell development but disrupts the marginal sinus and induces HEV-like structures in the spleen

Blood ◽

10.1182/blood-2007-02-075143 ◽

2007 ◽

Vol 110 (7) ◽

pp. 2381-2389 ◽

Cited By ~ 38

Author(s):

Feng Guo ◽

Debra Weih ◽

Elke Meier ◽

Falk Weih

Keyword(s):

Cell Adhesion ◽

B Cells ◽

B Cell ◽

Adhesion Molecule ◽

Cell Adhesion Molecule ◽

Marginal Zone ◽

Cell Development ◽

B Cell Development ◽

Marginal Sinus ◽

Cell Adhesion Molecule 1

Nuclear factor-κB (NF-κB) plays a crucial role in B-cell and lymphoid organ development. Here, we studied the consequences of constitutive, signal-independent activation of the alternative NF-κB pathway for the splenic marginal zone (MZ). In contrast to nfkb2−/− mice, which lack both p100 and p52, mice that lack only the inhibitory p100 precursor but still express the p52 subunit of NF-κB2 (p100−/−) had markedly elevated MZ B-cell numbers. Both cell-intrinsic mechanisms and increased stromal expression of vascular cell adhesion molecule-1 (VCAM-1) contributed to the accumulation of MZ B cells in p100−/− spleens. While migration of p100−/− MZ B cells toward the lysophospholipid sphingosine-1 phosphate (S1P) was not affected, CXCL13-stimulated chemotaxis was impaired, correlating with reduced migration of MZ B cells into follicles in response to lipopolysaccharide (LPS). Strikingly, p100 deficiency resulted in the absence of a normal marginal sinus, strongly induced expression of mucosal addressin cell adhesion molecule-1 (MAdCAM-1) and glycosylated cell adhesion molecule-1 (GlyCAM-1), and the formation of nonfunctional ectopic high endothelial venule (HEV)–like structures in the red pulp. Thus, constitutive activation of the alternative NF-κB pathway favors MZ B-cell development and accumulation but leads to a disorganized spleen microarchitecture.

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Conditional Vascular Cell Adhesion Molecule 1 Deletion in Mice

Journal of Experimental Medicine ◽

10.1084/jem.193.6.741 ◽

2001 ◽

Vol 193 (6) ◽

pp. 741-754 ◽

Cited By ~ 343

Author(s):

Pandelakis A. Koni ◽

Sunil K. Joshi ◽

Ulla-Angela Temann ◽

Dian Olson ◽

Linda Burkly ◽

...

Keyword(s):

T Cells ◽

Cell Adhesion ◽

B Cells ◽

B Cell ◽

Adhesion Molecule ◽

Cell Adhesion Molecule ◽

Vascular Cell Adhesion ◽

Vascular Cell ◽

Cell Numbers ◽

Deficient Mice

We generated vascular cell adhesion molecule (VCAM)-1 “knock-in” mice and Cre recombinase transgenic mice to delete the VCAM-1 gene (vcam-1) in whole mice, thereby overcoming the embryonic lethality seen with conventional vcam-1–deficient mice. vcam-1 knock-in mice expressed normal levels of VCAM-1 but showed loss of VCAM-1 on endothelial and hematopoietic cells when interbred with a “TIE2Cre” transgene. Analysis of peripheral blood from conditional vcam-1–deficient mice revealed mild leukocytosis, including elevated immature B cell numbers. Conversely, the bone marrow (BM) had reduced immature B cell numbers, but normal numbers of pro-B cells. vcam-1–deficient mice also had reduced mature IgD+ B and T cells in BM and a greatly reduced capacity to support short-term migration of transferred B cells, CD4+ T cells, CD8+ T cells, and preactivated CD4+ T cells to the BM. Thus, we report an until now unappreciated dominant role for VCAM-1 in lymphocyte homing to BM.

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Ki-B5: a monoclonal antibody unrelated to CD45 recognizes normal and neoplastic human B cells in routine paraffin sections

Blood ◽

10.1182/blood.v77.4.809.809 ◽

1991 ◽

Vol 77 (4) ◽

pp. 809-817 ◽

Cited By ~ 14

Author(s):

ML Hansmann ◽

HH Wacker ◽

J Gralla ◽

H Lumbeck ◽

M Kossmahl ◽

...

Keyword(s):

Monoclonal Antibody ◽

T Cell ◽

B Cells ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Protein Fractions ◽

Paraffin Sections ◽

Human B Cells ◽

Normal Human

Abstract In the search for immunoreagents appropriate for the histopathologic diagnosis of malignant B-cell lymphomas in routinely processed paraffin sections, a new monoclonal antibody, Ki-B5, was generated using a high- grade B-cell lymphoma as the immunogene. Ki-B5 is a mouse IgG1/kappa that recognizes five protein fractions of about 84, 82, 55, 48, and 27 Kd after biosynthetic radiolabeling and immunoprecipitation. Protein fractions with the molecular weights of approximately 84 and 82 Kd were expressed on the cell surface and show that Ki-B5 is probably unrelated to CD45. It was possible through electron microscopy to visualize the membrane-bound portion of Ki-B5. Extensive immunohistologic studies on normal human tissue and various neoplasias demonstrated the high specificity of Ki-B5 to normal human B cells and a minor subgroup of plasma cells. Except for ML-2, which is a myelomonocytic human cell line, Ki-B5 exclusively recognized the B-cell lineage, including EB-3, BALL-1, and NALM-1. All carcinomas, sarcomas, and malignant melanomas tested with Ki-B5 were negative. Although normal granulocytes and monocytes were constantly negative, three of eight myelomonocytic leukemias coreacted with this antibody. Eight of the 57 T-cell lymphomas studied were positive to Ki-B5. Five were classified as lymphoblastic, two represented T8-CLL, and one was classified as immunoblastic T-cell lymphoma. Only 3 of 126 cases of B-cell lymphoma, including rare types not considered in the current classifications, were negative to Ki-B5. Plasmacytomas were also negative, except for one case. Irrespective of the cases of lymphoblastic lymphoma and plasmacytoma, Ki-B5 represents a new monoclonal antibody appropriate for the diagnosis and immunophenotyping of malignant lymphomas in routinely processed paraffin sections.

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MALT1 and the API2-MALT1 fusion act between CD40 and IKK and confer NF-κB-dependent proliferative advantage and resistance against FAS-induced cell death in B cells

Blood ◽

10.1182/blood-2004-06-2297 ◽

2005 ◽

Vol 105 (7) ◽

pp. 2891-2899 ◽

Cited By ~ 56

Author(s):

Liza Ho ◽

R. Eric Davis ◽

Béatrice Conne ◽

Richard Chappuis ◽

Margaret Berczy ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Nuclear Factor Κb ◽

Membrane Lipid ◽

Dominant Negative ◽

Non Hodgkin Lymphoma ◽

Human B Cells ◽

Iκb Kinase

AbstractThe most frequently recurring translocations in mucosa-associated lymphoid tissue (MALT) B-cell non-Hodgkin lymphoma, t(11;18)(q21;q21) and t(14;18)(q32; q21), lead to formation of an API2-MALT1 fusion or IgH-mediated MALT1 overexpression. Various approaches have implicated these proteins in nuclear factor κB (NF-κB) signaling, but this has not been shown experimentally in human B cells. Immunohistochemistry showed that MALT1 is predominantly expressed in normal and malignant germinal center B cells, corresponding to the differentiation stage of MALT lymphoma. We expressed MALT1 and apoptosis inhibitor-2 API2/MALT1 in human B-cell lymphoma BJAB cells and found both transgenes in membrane lipid rafts along with endogenous MALT1 and 2 binding partners involved in NF-κB signaling, B-cell lymphoma 10 (BCL10) and CARMA1 (caspase recruitment domain [CARD]-containing membrane-associated guanylate kinase [MAGUK] 1). API2-MALT1 and exogenous MALT1 increased constitutive NF-κB activity and enhanced IκB kinase (IKK) activation induced by CD40 stimulation. Both transgenes protected BJAB cells from FAS (CD95)-induced death, consistent with increases in NF-κB cytoprotective target gene expression, and increased their proliferation rate. Expression of a dominant-negative IκBα mutant showed that these survival and proliferative advantages are dependent on elevated constitutive NF-κB activity. Our findings support a model in which NF-κB signaling, once activated in a CD40-dependent immune response, is maintained and enhanced through deregulation of MALT1 or formation of an API2-MALT1 fusion.

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The small FOXP1 isoform predominantly expressed in activated B cell-like diffuse large B-cell lymphoma and full-length FOXP1 exert similar oncogenic and transcriptional activity in human B cells

Haematologica ◽

10.3324/haematol.2016.156455 ◽

2016 ◽

Vol 102 (3) ◽

pp. 573-583 ◽

Cited By ~ 7

Author(s):

Martine van Keimpema ◽

Leonie J. Grüneberg ◽

Esther J.M. Schilder-Tol ◽

Monique E.C.M. Oud ◽

Esther A. Beuling ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Transcriptional Activity ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Full Length ◽

Large B Cell Lymphoma ◽

Human B Cells ◽

Large B Cell

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Aging predisposes B cells to malignancy by activating c-Myc and perturbing the genome and epigenome

10.1101/2021.02.23.432500 ◽

2021 ◽

Author(s):

Anastasia V. Shindyapina ◽

José P. Castro ◽

Alessandro Barbieri ◽

Olga S. Strelkova ◽

João A. Paulo ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Cell Lymphoma ◽

Human Cancer ◽

Laboratory Mouse ◽

B Cell Lymphoma ◽

Mouse Strains ◽

Human B Cells ◽

Early Markers ◽

Established Cell

AbstractAge is the single major risk factor for human cancer; however, naturally occurring cancers are rarely studied in aged animal models. Laboratory mouse strains spontaneously develop cancer with age and some predominantly die from B-cell lymphoma. Here, we uncover how B-cell lymphoma develops as a consequence of the aging immune system. We found that aged B cells undergo clonal expansions driven by genetic and epigenetic changes and established cell and spleen size as early markers of malignant transformation. High-throughput and omics assays of aged B cells and the use of mouse models revealed that c-Myc is a master regulator of B cell size and clonal expansion. A single-cell RNA-seq analysis suggested that clonal B cells originate from age-associated B cells, memory B cells that accumulate during aging. Further studies showed that c-Myc becomes activated in B cells in response to the aging microenvironment. Thus, c-Myc, aging environment, somatic mutations and the epigenome cooperate to give rise to clonal age-accelerated B cells, which we named Myc+ cells. We further show the relevance of this model to aged human B cells in blood and spleen. This study characterized a first mouse model that captures a natural transition of B cells to a prevalent type of cancer during aging.

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