Lyn Signaling To Upregulate GANP Is Critical for the Survival of High-Affinity B Cells in Germinal Centers of Lymphoid Organs

Kuwahara, K.; Nakaya, Teruo; Phimsen, Suchada; Toda, Teppei; Kitabatake, Masahiro; Kaji, Tomohiro; Takemori, Toshitada; Watanabe, Takeshi; Sakaguchi, Nobuo

doi:10.4049/jimmunol.1200649

Cited by 7 publications

(6 citation statements)

References 35 publications

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“…Recently, it has gradually been revealed that GANP possesses multiple functions. Previous report indicated that GANP upregulation is essential for the survival of mature germinal center B-cells with high affinity type due to suppression of DNA damages [9]. Taken together with the previous and present results, GANP may also be required for the survival of HRS cells originated from germinal center B-cells of lg-ganp Tg mice.…”

Section: Discussionsupporting

confidence: 90%

“…Our study suggests that GANP plays an important role in the transdifferentiation or reprograming of B cells to macrophage-like cells and the consequent development of B-cell/macrophage biphenotypic Hodgkinoid lymphoma that corresponds to human HL. Our previous report indicated that GANP, one of the targets of Lyn-mediated signaling, is most likely regulated via the PU.1 binding site of the ganp promoter region [9,17]. Because PU.1 exerts shared transcriptional regulation of both B-cell and macrophage differentiation [18,19], PU.1 may modulate the dynamic reprogramming between B-cell and macrophage differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…Lyn is involved in signal transduction of intracytoplasmic molecules (such as sIgM and CD40) expressed on B cells in the peripheral lymphoid organs [6]. Germinal center-associated nuclear protein (GANP) is one of the targets of Lyn-mediated signaling in germinal center B cells for high antibody affinity maturation [7][8][9]. Abnormal overexpression of GANP has been reported in various human hematopoietic and lymphoid neoplasms including HRS cells in HL [10]; this suggests that Lyn-target GANP plays a regulatory role in the transdifferentiation or reprograming of B cells to macrophage-like cells.…”

Section: Introductionmentioning

confidence: 99%

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A Novel Cytological Model of B-Cell/Macrophage Biphenotypic Cell Hodgkin Lymphoma in Ganp-Transgenic Mice

Sakai

Rezano

Okada

et al. 2020

Cancers

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Hodgkin lymphoma (HL) is one of the most difficult neoplasms in terms of cytopathological research owing to the lack of established cytological murine models. Although HL is believed to be of lymphoid germinal center B-cell origin, HL cells exhibit unique biphenotypic characteristics of B cells and macrophages. B-cell/macrophage biphenotypic cells have also been identified in the spleen of Lyn-deficient mice. Moreover, Lyn-targeting germinal center-associated nuclear protein (GANP)-transgenic mice (Ig-ganpTg mice) spontaneously develop a lymphoid tumor. We aimed to investigate whether the lymphoid tumor developed in Ig-ganpTg mice exhibit biphenotypic characteristics of B cells/macrophages that correspond to human HL. Here, we demonstrated GANP overexpression in human HL cells and found that it may regulate transdifferentiation between B cells and macrophages. We also demonstrated that tumors were comparable with B-cell/macrophage biphenotypic Hodgkinoid lymphomas. The tumor cells expressed macrophage-related F4/80, CD68, and CD204 as well as cytoplasmic B220 and µ-/κ-chains; in addition, these cells exhibited phagocytic activity. These cells also expressed transcripts of CD30; c-fms; and the cytokines monocyte chemoattractant protein (MCP)-1, MCP-5, RANTES, tumor necrosis factor-α and thrombopoietin associated with macrophages as well as granulocyte/macrophage colony-stimulating factor, interleukin (IL)-4, IL-10, IL-12, and IL-13. Ig-ganpTg mice represent a novel cytological model for the study of cytopathological etiology and oncogenesis of HL.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Novel Cytological Model of B-Cell/Macrophage Biphenotypic Cell Hodgkin Lymphoma in Ganp-Transgenic Mice

Sakai

Rezano

Okada

et al. 2020

Cancers

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“…The effect of dasatinib in reducing the splenic follicle size (Fig. 3E) prompted an investigation of germinal center (GC) cells, a rapidly proliferating population of B cells that is dependent on Lyn kinase signaling [35]–[37]. We found that dasatinib caused a significant reduction of B220 + cells expressing the GC markers CD95 and GL7 (Fig.…”

Section: Resultsmentioning

confidence: 95%

Dasatinib Targets B-Lineage Cells but Does Not Provide an Effective Therapy for Myeloproliferative Disease in c-Cbl RING Finger Mutant Mice

et al. 2014

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This study aimed to determine whether the multi-kinase inhibitor dasatinib would provide an effective therapy for myeloproliferative diseases (MPDs) involving c-Cbl mutations. These mutations, which occur in the RING finger and linker domains, abolish the ability of c-Cbl to function as an E3 ubiquitin ligase and downregulate activated protein tyrosine kinases. Here we analyzed the effects of dasatinib in a c-Cbl RING finger mutant mouse that develops an MPD with a phenotype similar to the human MPDs. The mice are characterized by enhanced tyrosine kinase signaling resulting in an expansion of hematopoietic stem cells, multipotent progenitors and cells within the myeloid lineage. Since c-Cbl is a negative regulator of c-Kit and Src signaling we reasoned that dasatinib, which targets these kinases, would be an effective therapy. Furthermore, two recent studies showed dasatinib to be effective in inhibiting the in vitro growth of cells from leukemia patients with c-Cbl RING finger and linker domain mutations. Surprisingly we found that dasatinib did not provide an effective therapy for c-Cbl RING finger mutant mice since it did not suppress any of the hematopoietic lineages that promote MPD development. Thus we conclude that dasatinib may not be an appropriate therapy for leukemia patients with c-Cbl mutations. We did however find that dasatinib caused a marked reduction of pre-B cells and immature B cells which correlated with a loss of Src activity. This study is therefore the first to provide a detailed characterization of in vivo effects of dasatinib in a hematopoietic disorder that is driven by protein tyrosine kinases other than BCR-ABL.

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“…6B-6D). The effect of dasatinib on germinal center (GC) B cells was also examined, since they are highly proliferative and dependent on Lyn kinase signaling [36][37][38]. Dasatinib was associated with a significant reduction of B220 þ cells that express the GC markers CD95 and GL7 (Fig.…”

Section: Dasatinib Targets Immature B Cells In the Spleenmentioning

confidence: 99%

The targeting of human and mouse B lymphocytes by dasatinib

Oksvold

Duyvestyn

Dagger

et al. 2015

Experimental Hematology

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Dasatinib inhibits B-cell receptor-Abelson murine leukemia viral oncogene homologue 1, Src, and other tyrosine kinases. Few studies have addressed the impact of dasatinib on normal blood cells, especially in vivo. Here we show that dasatinib leads to a reduced number of human CD19+ peripheral B cells owing to a strong induction of apoptosis. In contrast, no similar effect on T-cell viability was observed. However, dasatinib induced a comparable broad inhibition of the early events of B- and T-cell receptor signaling. Furthermore, dasatinib was shown to be a more pronounced inhibitor of both basal and B-cell receptor-induced activity of Bruton's tyrosine kinase and PLCγ2 compared with the more specific Bruton's tyrosine kinase inhibitor ibrutinib. Human progenitor B cells from the pre-B stage were sensitive to dasatinib. In an in vivo murine model, dasatinib reduced B-lineage cells in the bone marrow with a marked effect on the pre-B subpopulation. Dasatinib led to a reduced spleen size, with a loss of large immature transitional immunoglobulin M(+)/immunoglobulin D(-) B cells and a reduction in germinal center B cells. Dasatinib caused a marked loss of thymocytes without affecting myeloid lineage cells or hematopoietic progenitors. This study reveals important side effects of dasatinib with specific loss of activated B and thymocyte populations, which may have an impact during long-term treatment.

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Lyn Signaling To Upregulate GANP Is Critical for the Survival of High-Affinity B Cells in Germinal Centers of Lymphoid Organs

Cited by 7 publications

References 35 publications

A Novel Cytological Model of B-Cell/Macrophage Biphenotypic Cell Hodgkin Lymphoma in Ganp-Transgenic Mice

A Novel Cytological Model of B-Cell/Macrophage Biphenotypic Cell Hodgkin Lymphoma in Ganp-Transgenic Mice

Dasatinib Targets B-Lineage Cells but Does Not Provide an Effective Therapy for Myeloproliferative Disease in c-Cbl RING Finger Mutant Mice

The targeting of human and mouse B lymphocytes by dasatinib

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