SIGLEC-G deficiency increases susceptibility to develop B-cell lymphoproliferative disorders

Simonetti, Giorgia; Bertilaccio, Maria Teresa Sabrina; Rodriguez, Tania Veliz; Apollonio, Benedetta; Dagklis, Antonis; Rocchi, Martina; Innocenzi, A; Winkler, Thomas; Nitschke, Lars; Ponzoni, Maurilio; Caligaris-Cappio, Federico

doi:10.3324/haematol.2013.100230

Cited by 9 publications

(9 citation statements)

References 43 publications

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“…Several recent reports suggest that siglec deficiencies can increase the potential for generation of lymphomas and leukemias 107, 108 . Moreover, in keeping with their roles aiding immune cells in distinguishing between self and non-self, Siglecs are emerging as playing a role in regulation of immune surveillance of cancer.…”

Section: Siglecs In Immune Surveillance Of Cancermentioning

confidence: 99%

Siglec-mediated regulation of immune cell function in disease

2014

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All mammalian cells display a diverse array of glycan structures that differ from those found on microbial pathogens. Siglecs are a family of sialic acid-binding immunoglobulin-like receptors that participate in the discrimination of ‘self’ and ‘non-self’ and regulate the functions of cells in the innate and adaptive immune systems through recognition of their glycan ligands. In this review, we describe the recent advances in our understanding of the roles of Siglecs in the regulation of immune cell functions in infectious diseases, inflammation, neurodegeneration, autoimmune diseases and cancer.

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Section: Siglecs In Immune Surveillance Of Cancermentioning

confidence: 99%

Siglec-mediated regulation of immune cell function in disease

2014

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“…These aMyIIA B1a cells ultimately transformed into malignant cells with the characteristic of mature cells, with decreased Siglec-G expression ( Figure 6I ). The reduced Siglec-G expression may contribute to pathogenesis, since Siglec-G deficiency increases B-cell lymphoproliferative disorders ( 46 ). Thus, the increased Arid3a in Lin28b + Let7 − outcome at the pre-B cell stage allowed the generation of SLC-unassociated autoreactive BCR B1a cells from adult BM, and ultimately support the ability to develop B1a cell tumors (summarized in Figure 6J ).…”

Section: Resultsmentioning

confidence: 99%

Crucial Role of Increased Arid3a at the Pre-B and Immature B Cell Stages for B1a Cell Generation

Hayakawa

Shinton

et al. 2019

Front. Immunol.

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The Lin28b+Let7− axis in fetal/neonatal development plays a role in promoting CD5+ B1a cell generation as a B-1 B cell developmental outcome. Here we identify the Let7 target, Arid3a, as a crucial molecular effector of the B-1 cell developmental program. Arid3a expression is increased at pro-B cell stage and markedly increased at pre-B and immature B cell stages in the fetal/neonatal liver B-1 development relative to that in the Lin28b−Let7+ adult bone marrow (BM) B-2 cell development. Analysis of B-lineage restricted Lin28b transgenic (Tg) mice, Arid3a knockout and Arid3a Tg mice, confirmed that increased Arid3a allows B cell generation without requiring surrogate light chain (SLC) associated pre-BCR stage, and prevents MHC class II cell expression at the pre-B and newly generated immature B cell stages, distinct from pre-BCR dependent B development with MHC class II in adult BM. Moreover, Arid3a plays a crucial role in supporting B1a cell generation. The increased Arid3a leads higher Myc and Bhlhe41, and lower Siglec-G and CD72 at the pre-B and immature B cell stages than normal adult BM, to allow BCR signaling induced B1a cell generation. Arid3a-deficiency selectively blocks the development of B1a cells, while having no detectable effect on CD5− B1b, MZ B, and FO B cell generation resembling B-2 development outcome. Conversely, enforced expression of Arid3a by transgene is sufficient to promote the development of B1a cells from adult BM. Under the environment change between birth to adult, altered BCR repertoire in increased B1a cells occurred generated from adult BM. However, crossed with B1a-restricted VH/D/J IgH knock-in mice allowed to confirm that SLC-unassociated B1a cell increase and CLL/lymphoma generation can occur in aged from Arid3a increased adult BM. These results confirmed that in fetal/neonatal normal mice, increased Arid3a at the pre-B cell and immature B cell stages is crucial for generating B1a cells together with the environment for self-ligand reactive BCR selection, B1a cell maintenance, and potential for development of CLL/Lymphoma in aged mice.

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“…In our analysis, we found that all siglecs including siglec-1 to siglec-9 were significantly suppressed in HCC tumors, which may serve as anti-oncogenes. Recently, several studies revealed that siglec deficiencies contributed to the potential for generation of malignancy like lymphomas and leukemias [ 17 , 18 ]. As reviewed by Macauley et al, siglecs played a role in regulating of immune surveillance of cancer by keeping with their roles aiding immune cells in distinguishing between self and non-self [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

“…Siglecs including siglec-2 have been reported to regulate cell growth and survival, by both inhibition of proliferation and/or induction of apoptosis [ 13 ]. Throughout the last decade, several novel therapeutic agents that target siglec-2 are being developed as an alternative approach for cancer treatment [ 17 , 18 , 30 ]. Previous reports showed that siglec-2 as a B-cell-associated adhesion protein appeared to play a critical role in establishing signaling thresholds for B-cell activation, mediating normal antibody response to thymus-independent antigens and regulating the lifespan of mature B cells [ 31 , 32 ].…”

Section: Discussionmentioning

confidence: 99%

Down-regulation of siglec-2 (CD22) predicts worse overall survival from HBV-related early-stage hepatocellular carcinoma: a preliminary analysis from Gene Expression Omnibus

Ren

Jiang

et al. 2018

Bioscience Reports

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Sialic-acid-binding immunoglobulin-like lectin (siglec) regulates cell death, anti-proliferative effects and mediates a variety of cellular activities. Little was known about the relationship between siglecs and hepatocellular carcinoma (HCC) prognosis. Siglec gene expression between tumor and non-tumor tissues were compared and correlated with overall survival (OS) from HCC patients in GSE14520 microarray expression profile. Siglec-1 to siglec-9 were all down-regulated in tumor tissues compared with those in non-tumor tissues in HCC patients (all P < 0.05). Univariate and multivariate Cox regression analysis revealed that siglec-2 overexpression could predict better OS (HR = 0.883, 95%CI = 0.806–0.966, P = 0.007). Patients with higher siglec-2 levels achieved longer OS months than those with lower siglec-2 levels in the Kaplan–Meier event analysis both in training and validation sets (P < 0.05). Alpha-fetoprotein (AFP) levels in siglec-2 low expression group were significantly higher than those in siglec-2 high expression group using Chi-square analysis (P = 0.043). In addition, both logistic regression analysis and ROC curve method showed that siglec-2 down-regulation in tumor tissues was significantly associated with AFP elevation over 300 ng/ml (P < 0.05). In conclusion, up-regulation of siglec-2 in tumor tissues could predict better OS in HCC patients. Mechanisms of siglec-2 in HCC development need further research.

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SIGLEC-G deficiency increases susceptibility to develop B-cell lymphoproliferative disorders

Cited by 9 publications

References 43 publications

Siglec-mediated regulation of immune cell function in disease

Siglec-mediated regulation of immune cell function in disease

Crucial Role of Increased Arid3a at the Pre-B and Immature B Cell Stages for B1a Cell Generation

Down-regulation of siglec-2 (CD22) predicts worse overall survival from HBV-related early-stage hepatocellular carcinoma: a preliminary analysis from Gene Expression Omnibus

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