The sialyltransferase ST3GAL6 influences homing and survival in multiple myeloma

Glavey, Siobhán; Manier, Salomon; Natoni, Alessandro; Sacco, Antonio; Moschetta, Michele; Reagan, Michaela R.; Murillo, Laura S.; Şahin, İlyas; Wu, Ping; Mishima, Yuji; Zhang, Yu; Zhang, Wenjing; Zhang, Yong; Morgan, Gareth J.; Joshi, Lokesh; Roccaro, Aldo M.; Ghobrial, Irène M.; O’Dwyer, Michael

doi:10.1182/blood-2014-03-560862

Cited by 105 publications

(97 citation statements)

References 41 publications

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“…Knockdown of Neu1 was able to enhance tolerance and overexpression of Neu1 or treatment with sialidase abrogated tolerance. Furthermore, in addition to the decrease expression of the Neu1, we also found the expression of sialyltransferase ST3 Gal6 was specifically increased on tolerant RAW 264.7 cells, the action of which adds sialic acid to the terminal portions of the glycolipids or glycoproteins via ␣-2,3 linkages (30).…”

Section: Discussionmentioning

confidence: 81%

Induction of Siglec-1 by Endotoxin Tolerance Suppresses the Innate Immune Response by Promoting TGF-β1 Production

Lan

Ren

et al. 2016

Journal of Biological Chemistry

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Sepsis is one of the leading causes of death worldwide. Although the prevailing theory for the sepsis syndrome is a condition of uncontrolled inflammation in response to infection, sepsis is increasingly being recognized as an immunosuppressive state known as endotoxin tolerance. We found sialylation of cell surface was significantly increased on LPS-induced tolerant cells; knockdown of Neu1 in macrophage cell line RAW 264.7 cells resulted in enhanced LPS-induced tolerance, whereas overexpression of Neu1 or treatment with sialidase abrogated LPS-induced tolerance, as defined by measuring TNF-␣ levels in the culture supernatants. We also found that the expression of Siglec-1 (a member of sialic acid-binding Ig (I)-like lectin family members, the predominant sialic acid-binding proteins on cell surface) was specifically up-regulated in endotoxin tolerant cells and the induction of Siglec-1 suppresses the innate immune response by promoting TGF-␤1 production. The enhanced TGF-␤1 production by Siglec-1 was significantly attenuated by spleen tyrosine kinase (Syk) inhibitor. Knockdown of siglec-1 in RAW 264.7 cells resulted in inhibiting the production of TGF-␤1 by ubiquitin-dependent degradation of Syk. Mechanistically, Siglec-1 associates with adaptor protein DNAX-activation protein of 12 kDa (DAP12) and transduces a signal to Syk to control the production of TGF-␤1 in endotoxin tolerance. Thus, Siglec-1 plays an important role in the development of endotoxin tolerance and targeted manipulation of this process could lead to a new therapeutic opportunity for patients with sepsis.Sepsis is generally defined as a systemic inflammatory response syndrome in response to infection. Sepsis can be potentially life threatening; of more than 1 million Americans who are diagnosed with severe sepsis every year, between 28 and 50% will die from this disease (1, 2). It is well-recognized that patients with sepsis are often immune suppressed, a state of reduced responsiveness to endotoxin known as endotoxin tolerance, deaths in this immunosuppressive phase are typically due to failure to control the secondary infections (3-5). The molecular mechanisms underlying this endotoxin tolerance phenomenon is poorly understood.Sialic acids are a family of nine-carbon acidic monosaccharides and are involved in immune response, such as host-pathogen recognition, migration, and antigen presentation. Mounting experimental evidence suggests that the presence of sialic acid residue act as a marker of self in the immune system, as such residues are absent from most microbes (6). Indeed, host cells can be lysed by immune cytotoxic effector mechanisms after extensive desialylation, an observation that demonstrates the significant role played by cell surface sialic acids in the selfrecognition process (7). In addition, normal human serum contains natural antibodies to sialidase-treated red blood cells (7-9), lymphocytes (10), and thymocytes (7). Recently, Meesmann et al. showed that desialylation acted as an "eat me" signal and caused an enhanced upt...

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Section: Discussionmentioning

confidence: 81%

Induction of Siglec-1 by Endotoxin Tolerance Suppresses the Innate Immune Response by Promoting TGF-β1 Production

Lan

Ren

et al. 2016

Journal of Biological Chemistry

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“…Furthermore, migration and invasion of MM cells to BM may require the E/P-selectins and their common receptor P-selectin glycoprotein ligand-1 (23). Other factors, such as the integrin ITGAL, the sialyltransferase ST3GAL6, and SDC1, may also contribute to MM BM homing (11,24,25). Our study reveals for the first time that autocrine MIF in MM cells is an important player in MM cell affinity to BM.…”

Section: Discussionmentioning

confidence: 84%

“…In vivo confocal microscopy was performed as described (11). Further details are given in the Supplementary Materials (available online).…”

Section: In Vivo Confocal Microscopymentioning

confidence: 99%

Role of Myeloma-Derived MIF in Myeloma Cell Adhesion to Bone Marrow and Chemotherapy Response

Zheng

Wang

et al. 2016

JNCI J Natl Cancer Inst

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Background: Multiple myeloma (MM) remains an incurable cancer characterized by accumulation of malignant plasma cells in the bone marrow (BM). The mechanism underlying MM homing to BM is poorly elucidated. Methods: The clinical significance of migration inhibitory factor (MIF) expression was examined by analyzing six independent gene expression profile databases of primary MM cells using the Student's t test and Kaplan-Meier test. Enzymelinked immunosorbent assay was used to examine MIF expression. In vivo bioluminescent imaging was used to determine MM cell localization and treatment efficacy in human MM xenograft mouse models, with three to four mice per group. MM cell attachment to BM stromal cells (BMSCs) was monitored by cell adhesion assay. MIF regulation of the expression of adhesion molecules was determined by chromatin immunoprecipitation (ChIP) assay. Statistical tests were two-sided. Results: High levels of MIF were detected in MM BM (MIF level in BM plasma: healthy ¼ 10.72 6 5.788 ng/mL, n ¼ 5; MM ¼ 1811 6 248.7 ng/mL, n ¼ 10; P < .001) and associated with poor survival of patients (Kaplan-Meier test for MM OS: 87 MIF high patients, 86 MIF low patients, P ¼ .02). Knocking down MIF impaired MM cell adhesion to BMSCs in vitro and led to formation of extramedullary tumors in SCID mice. MIF acted through surface receptor CXCR4 and adaptor COPS5 to regulate the expression of adhesion molecules ALCAM, ITGAV, and ITGB5 on MM cells. More importantly, MIF-deficient MM cells were sensitive to chemotherapy in vitro when cocultured with BMSCs and in vivo. MIF inhibitor 4-IPP sensitized MM cells to chemotherapy. Conclusions: MIF is an important player and a novel therapeutic target in MM. Inhibiting MIF activity will sensitize MM cells to chemotherapy.

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“…107 Messenger RNA and microRNA signatures, as well as exosome content and volume from bone marrow stroma, were also found to be abnormal in samples from patients with multiple myeloma. 104,108 Notch receptor signalling 109 (a critical regulator of HSC fate and differentiation in the bone marrow) and the SDF1–CXCR4 axis are often deviant, 110 extracellular matrix components and ratios are often abnormal, 111 and changes in glycosylation of cell-surface adhesion molecules such as selectin ligands, integrins and mucins, 112 in cells of the bone marrow are often observed in malignant niches.…”

Section: Cancer-related Disruption Of the Nichementioning

confidence: 99%

Navigating the bone marrow niche: translational insights and cancer-driven dysfunction

2015

Self Cite

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The bone marrow niche consists of stem and progenitor cells destined to become mature cells such as haematopoietic elements, osteoblasts or adipocytes. Marrow cells, influenced by endocrine, paracrine and autocrine factors, ultimately function as a unit to regulate bone remodelling and haematopoiesis. Current evidence highlights the bone marrow niche is not merely an anatomic compartment; rather, it integrates the physiology of two distinct organ systems, the skeleton and the marrow. The niche has a hypoxic microenvironment that maintains quiescent haematopoietic stem cells (HSCs) and supports glycolytic metabolism. In response to biochemical cues and under the influence of neural, hormonal, and biochemical factors, marrow stromal elements, such as mesenchymal stromal cells (MSCs), differentiate into mature, functioning cells. However, disruption of the niche can affect cellular differentiation, resulting in disorders ranging from osteoporosis to malignancy. In this Review, we propose that the niche reflects the vitality of two distinct tissues—bone and blood—by providing a unique environment for stem and stromal cells to flourish whilst simultaneously preventing disproportionate proliferation, malignant transformation or loss of the multipotent progenitors required for healing, functional immunity and growth throughout an organism’s lifetime. Through a fuller understanding of the complexity of the niche in physiologic and pathologic states, the successful development of more-effective therapeutic approaches to target the niche and its cellular components for the treatment of rheumatic, endocrine, neoplastic and metabolic diseases becomes achievable.

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The sialyltransferase ST3GAL6 influences homing and survival in multiple myeloma

Cited by 105 publications

References 41 publications

Induction of Siglec-1 by Endotoxin Tolerance Suppresses the Innate Immune Response by Promoting TGF-β1 Production

Induction of Siglec-1 by Endotoxin Tolerance Suppresses the Innate Immune Response by Promoting TGF-β1 Production

Role of Myeloma-Derived MIF in Myeloma Cell Adhesion to Bone Marrow and Chemotherapy Response

Navigating the bone marrow niche: translational insights and cancer-driven dysfunction

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