Regulatory Effects of Novel Neurotrophin-1/B Cell-Stimulating Factor-3 (Cardiotrophin-Like Cytokine) on B Cell Function

Senaldi, Giorgio; Stolina, Marina; Guo, Jane; Faggioni, Raffaella; McCabe, Susan; Kaufman, Stephen A.; Van, Gwyneth; Xu, Weixin; Fletcher, Frederick A.; Boone, Thomas C.; Chang, Ming Shi; Sarmiento, Ulla M.; Cattley, Russell C.

doi:10.4049/jimmunol.168.11.5690

Cited by 46 publications

(46 citation statements)

References 35 publications

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“…3A, B). CLCF1 encodes cardiotrophin-like-cytokine factor 1, which binds to CRLF1 to form a compound cytokine, eventually leading to activation of the JAK-STAT signaling and B-cell proliferation in vivo (Senaldi et al 2002;Crabe et al 2009;Savin et al 2015;Sims 2015). Important for lymphocyte development and activation, BTLA expression is highly regulated during B-cell differentiation and is also directly linked to B-cell receptor signaling cascade (Vendel et al 2009;Llinas et al 2011;Kannan et al 2015).…”

Section: Resultsmentioning

confidence: 99%

Whole-transcriptome sequencing identifies a distinct subtype of acute lymphoblastic leukemia with predominant genomic abnormalities of EP300 and CREBBP

et al. 2016

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Chromosomal translocations are a genomic hallmark of many hematologic malignancies. Often as initiating events, these structural abnormalities result in fusion proteins involving transcription factors important for hematopoietic differentiation and/or signaling molecules regulating cell proliferation and cell cycle. In contrast, epigenetic regulator genes are more frequently targeted by somatic sequence mutations, possibly as secondary events to further potentiate leukemogenesis. Through comprehensive whole-transcriptome sequencing of 231 children with acute lymphoblastic leukemia (ALL), we identified 58 putative functional and predominant fusion genes in 54.1% of patients (n = 125), 31 of which have not been reported previously. In particular, we described a distinct ALL subtype with a characteristic gene expression signature predominantly driven by chromosomal rearrangements of the ZNF384 gene with histone acetyltransferases EP300 and CREBBP. ZNF384-rearranged ALL showed significant up-regulation of CLCF1 and BTLA expression, and ZNF384 fusion proteins consistently showed higher activity to promote transcription of these target genes relative to wild-type ZNF384 in vitro. Ectopic expression of EP300-ZNF384 and CREBBP-ZNF384 fusion altered differentiation of mouse hematopoietic stem and progenitor cells and also potentiated oncogenic transformation in vitro. EP300-and CREBBP-ZNF384 fusions resulted in loss of histone lysine acetyltransferase activity in a dominant-negative fashion, with concomitant global reduction of histone acetylation and increased sensitivity of leukemia cells to histone deacetylase inhibitors. In conclusion, our results indicate that gene fusion is a common class of genomic abnormalities in childhood ALL and that recurrent translocations involving EP300 and CREBBP may cause epigenetic deregulation with potential for therapeutic targeting.

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Section: Resultsmentioning

confidence: 99%

Whole-transcriptome sequencing identifies a distinct subtype of acute lymphoblastic leukemia with predominant genomic abnormalities of EP300 and CREBBP

et al. 2016

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“…Moreover, mice overexpressing the cytokine show body weight loss and B-cell hyperplasia with an increase in serum IgG and IgM [43]. In addition, aged animals show impairment of renal function due to immune complex glomerulopathy.…”

Section: Discussionmentioning

confidence: 98%

“…This cytokine is known as novel neurotrophin-1/B-cell-stimulating factor-3 (NNT-1/BSF-3) or cardiotrophin-like cytokine (CLC) since it shares sequence homology with CT. Like the other family members, CLC binds to gp130 and leads to activation of STAT3 [27]. It shows neurotrophic as well as B-cell-stimulatory effects [43].…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective effects of cardiotrophin-like cytokine on retinal ganglion cells

Schuettauf

Zurakowski

Quinto

et al. 2005

Graefe's Arch Clin Exp Ophthalmo

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“…Animals were bled immediately before and on days 7, 14, and 21 after immunization. Serum was analyzed for anti-KLH IgG and anti-Pneumovax IgM by ELISA as previously described (26). For the KLH-specific splenocyte proliferation assay, spleens were removed on day 21 post-KLH sensitization and cultured in triplicate for 4 days culture (as described above) with supplement of 0, 0.1, 1, or 10 g/ml KLH in media.…”

Section: Induction Of Ag-specific Abs In Vivo and Ag-specific Prolifementioning

confidence: 99%

Continuous RANKL Inhibition in Osteoprotegerin Transgenic Mice and Rats Suppresses Bone Resorption without Impairing Lymphorganogenesis or Functional Immune Responses

Stolina¹,

Dwyer²,

Ominsky³

et al. 2007

The Journal of Immunology

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Receptor activator of NF-κB ligand (RANKL) is an essential mediator of osteoclast formation, function, and survival. The effects of RANKL are inhibited by a soluble decoy receptor called osteoprotegerin (OPG). Total ablation of RANKL in knockout mice leads to high bone mass, lymph node agenesis, and altered lymphocyte differentiation. In contrast, RANKL inhibition via OPG suppresses bone resorption but not inflammation in animal models of inflammatory bone loss. This suggests that the immune phenotype of RANKL knockout mice is related to total RANKL ablation. We hypothesized that prenatal RANKL inhibition via OPG overexpression would suppress bone resorption without influencing lymph node formation or subsequent immune responses. Transgenic rats were created, wherein soluble OPG was overexpressed by 100-fold vs wild type (WT) controls, by gestational day 11 (i.e., before lymph node formation). The structure of lymph nodes, spleen, and thymus of OPG-transgenic (OPG-Tg) animals were comparable to those of age-matched WT rats at gestational day 19 and in adulthood. The OPG-Tg neonates had elevated bone mass, confirming the prenatal inhibition of RANKL. Adult OPG-Tg rats and OPG-Tg mice exhibited no significant functional alterations relative to WT controls when subjected to immune challenges to test for altered innate and humoral responses (e.g., contact hypersensitivity to oxazolone, IgM response to Pneumovax, IgG response to keyhole limpet hemocyanin, or cytokine response to LPS). In summary, prenatal RANKL inhibition did not impair lymph node development, nor did continuous life-long RANKL inhibition cause obvious changes in innate or humoral immune responses in mice or rats.

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Regulatory Effects of Novel Neurotrophin-1/B Cell-Stimulating Factor-3 (Cardiotrophin-Like Cytokine) on B Cell Function

Cited by 46 publications

References 35 publications

Whole-transcriptome sequencing identifies a distinct subtype of acute lymphoblastic leukemia with predominant genomic abnormalities of EP300 and CREBBP

Whole-transcriptome sequencing identifies a distinct subtype of acute lymphoblastic leukemia with predominant genomic abnormalities of EP300 and CREBBP

Neuroprotective effects of cardiotrophin-like cytokine on retinal ganglion cells

Continuous RANKL Inhibition in Osteoprotegerin Transgenic Mice and Rats Suppresses Bone Resorption without Impairing Lymphorganogenesis or Functional Immune Responses

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