The BTB-kelch Protein KLHL6 Is Involved in B-Lymphocyte Antigen Receptor Signaling and Germinal Center Formation

Krøll, Jens; Shi, Xiaozhong; Caprioli, Arianna; Liu, Hong-Hsing; Waskow, Claudia; Lin, Keng Mean; Miyazaki, Toru; Rodewald, Hans Reimer; Sato, Thomas N.

doi:10.1128/mcb.25.19.8531-8540.2005

Cited by 62 publications

(56 citation statements)

References 33 publications

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“…9 The observations described here seem to confirm the distinct profile of lymphocyte- 3 Here we have analyzed relatively new germinalcenter markers such as KLHL6 and GCET1. KLHL6 is a BTB-kelch protein involved in germinal-center B-cell maturation, 10 whereas GCET1 (germinal-center B cell-expressed transcript-1) is thought to be expressed exclusively by neoplasms that arrested at the germinal-center stage of differentiation. 11 These markers were positive in most of the nodular lymphocyte-predominant Hodgkin's lymphoma cases, which is evidence of a germinal-center stage of differentiation in lymphocytic and/or histiocytic Reed-Sternberg cell variants.…”

Section: Discussionmentioning

confidence: 99%

“…12 Interestingly, mononuclear Hodgkin's cells and multinucleated ReedSternberg cells in lymphocyte-rich classical Hodgkin's lymphoma commonly express KLHL6 (69%, 11 of 16), a molecule that has been implicated in BCR signal transduction and in the formation of the full germinal-center response. 10 NF-kB activation is considered to be an important survival factor for mononuclear Hodgkin's cells and multinucleated Reed-Sternberg cells in classical Hodgkin's lymphoma, whereby the inactivation of factor NF-kB in Hodgkin's lymphoma cell lines leads to the apoptosis of neoplastic cells. 13,14 Different expression patterns of NF-kB subunits and related molecular factors have been shown in classical Hodgkin's lymphoma and nodular lymphocyte-predominant Hodgkin's lymphoma, with c-Rel protein, Rel-B, p-50, TRAF1, and MUM-1 being significantly more frequently expressed in the former.…”

Section: Discussionmentioning

confidence: 99%

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Lymphocyte-rich classical Hodgkin's lymphoma: distinctive tumor and microenvironment markers

et al. 2009

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The existence, diagnostic features, and the biological and clinical relevance of lymphocyte-rich classical Hodgkin's lymphoma remain controversial. A comparative marker analysis of lymphocyte-rich classical Hodgkin's lymphoma, nodular lymphocyte-predominance Hodgkin's lymphoma, and of other subtypes of classical Hodgkin's lymphoma was carried out. Markers were selected focusing on B-cell lineage and transcription program (OCT.1, OCT.2, BOB.1, BCL6, PAX-5, GCET1, KLHL6, and BLIMP1), the NF-jB signaling pathway (REL-B, C-REL, TRAF-1, p-50, and MUM-1) and the T-cell microenvironment (CD3, CD57, PD-1, CXCL-13, and CD10, BCL-6, CD23). Lymphocyte-rich classical Hodgkin's lymphoma cases displayed features intermediate between those of classical Hodgkin's lymphoma and nodular lymphocyte-predominance Hodgkin's lymphoma. The expression of B-cell transcription factors such as OCT.1, OCT.2, BOB.1, and BCL6 was more frequent in lymphocyte-rich classical Hodgkin's lymphoma than in classical Hodgkin's lymphoma. A follicular T-cell microenvironment was also identified in 50% of lymphocyte-rich classical Hodgkin's lymphoma cases. NF-kB markers were expressed at frequencies comparable with those observed in classical Hodgkin's lymphoma. The neoplastic cell immunophenotype and microenvironment in lymphocyte-rich classical Hodgkin's lymphoma closely mimic that which are observed in the outer zone of the germinal center, where B-cell blasts with germinal-center markers co-express CD30 and the B-cell transcription program, surrounded by follicular T-cell rosettes. Lymphocyte-rich classical Hodgkin's lymphoma seems to be characterized by a stronger expression of the B-cell transcription program by the neoplastic cells and by a follicular T-cell background, occupying an intermediate position between classical Hodgkin's lymphoma and nodular lymphocyte-predominance Hodgkin's lymphoma.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Lymphocyte-rich classical Hodgkin's lymphoma: distinctive tumor and microenvironment markers

et al. 2009

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“…Of note, we observed in all CLL co-cultured on an EC layer that, compared to the baseline condition, there was up-regulation of KLHL6, which is implicated in B-cell receptor signaling and germinal center formation and mutated in about 1.8% of cases of CLL. 39,40 In conclusion, we demonstrated that CLL cells interact with endothelium through α4b1/VCAM-1 and αLb2/ICAM axes and cell adhesion is necessary to trigger the survival signals on leukemic cells. CLL/EC physical contact profoundly modifies the transcriptional profile of leukemic cells and leads to the establishment of a complex network of soluble factors that seem to provide additional survival advantages.…”

Section: Discussionmentioning

confidence: 99%

Physical contact with endothelial cells through 1- and 2- integrins rescues chronic lymphocytic leukemia cells from spontaneous and drug-induced apoptosis and induces a peculiar gene expression profile in leukemic cells

Maffei

Fiorcari²,

Bulgarelli³

et al. 2011

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundChronic lymphocytic leukemia B cells display prolonged survival in vivo, but when cultured in vitro rapidly undergo spontaneous apoptosis. We hypothesize that interactions with endothelial cells in infiltrated tissues and during recirculation may have a pathogenic role in chronic lymphocytic leukemia. Design and MethodsWe evaluated apoptosis of leukemic cells after co-culture on a monolayer of human umbilical vein endothelial cells with addition of fludarabine and antibodies that block adhesion. Then, we compared microarray-based gene expression profiles between leukemic cells at baseline and after coculture. ResultsWe found that the endothelial layer protected leukemic cells from apoptosis inducing a 2-fold mean decrement in apoptotic cells after 2 days of co-culture. Moreover, the endothelial layer decreased the sensitivity of chronic lymphocytic leukemia B cells to fludarabine-induced apoptosis. Physical contact with endothelium mediated by both b1-and b2-integrins is essential for the survival advantage of leukemic cells. In particular, blocking CD106 on endothelial cells or CD18 on leukemic B cells led to the almost complete abrogation of the survival advantage (>70% inhibition of viability). However, a reduction of apoptosis was also measured in leukemic cells cultured in conditioned medium collected after 2 days of co-culture, implying that survival is partially mediated by soluble factors. Overall, the contact with endothelial cells modulated 1,944 genes in chronic lymphocytic leukemia B cells, establishing a peculiar gene expression profile: up-regulation of angiogenesis-related genes, an increase of genes involved in TGFb and Wnt signaling pathways, secretion of cytokines recruiting stromal cells and macrophages and up-regulation of antiapoptotic molecules such as Bcl2 and Survivin. ConclusionsOur study supports the notion that endothelial cells are major players in the chronic lymphocytic leukemia microenvironment. Adhesion to endothelium strongly supports survival, protects from drug-induced apoptosis and extensively modifies the gene expression profile of leukemic cells.

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“…MeTIL scores signaling on B cells and germinal center formation (39). INA and SEMA3B are best known for their role in neuronal development, but studies also linked them to immune-related functions (40,41).…”

Section: Prediction Of Survival Outcomes In Other Cancer Types With Tmentioning

confidence: 99%

DNA methylation–based immune response signature improves patient diagnosis in multiple cancers

Jeschke

Bizet

Desmedt

et al. 2017

Journal of Clinical Investigation

118

102

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The BTB-kelch Protein KLHL6 Is Involved in B-Lymphocyte Antigen Receptor Signaling and Germinal Center Formation

Cited by 62 publications

References 33 publications

Lymphocyte-rich classical Hodgkin's lymphoma: distinctive tumor and microenvironment markers

Lymphocyte-rich classical Hodgkin's lymphoma: distinctive tumor and microenvironment markers

Physical contact with endothelial cells through 1- and 2- integrins rescues chronic lymphocytic leukemia cells from spontaneous and drug-induced apoptosis and induces a peculiar gene expression profile in leukemic cells

DNA methylation–based immune response signature improves patient diagnosis in multiple cancers

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