The novel JAK inhibitor CYT387 suppresses multiple signalling pathways, prevents proliferation and induces apoptosis in phenotypically diverse myeloma cells

Monaghan, Katherine; Khong, Tiffany; Burns, Christopher J.; Spencer, Andrew

doi:10.1038/leu.2011.175

Cited by 75 publications

(53 citation statements)

References 36 publications

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“…Activation of the IL-6/IL-6R/GP130 complex is crucial for survival and proliferation of human myeloma (6,11,13), and the JAK/STAT3 pathway is a major target downstream of IL-6R/GP130 signaling (8,14). We therefore evaluated a series of BM biopsies from patients with MM, as well as biopsies from normal BM and MGUS, for expression of phosphorylated STAT3 (P-STAT3) in the ectopic L-GP130 expression could lead to a loss of differentiation and immature hematopoietic disease, or possibly to a plasma cell disorder, when overexpressed in hematopoietic stem/progenitor cells.…”

Section: Stat3 Phosphorylation and Target Gene Activation Is A Hallmamentioning

confidence: 99%

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GP130 activation induces myeloma and collaborates with MYC

Dechow¹,

Steidle²,

Götze³

et al. 2014

J. Clin. Invest.

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R e s e a R c h a R t i c l e5. Group 2 correlated with high STAT3 expression (i.e., STAT3 activation). (G) GSEA showed a significantly different distribution of the STAT3 activation-associated genes, with group 1 being negatively correlated (NES, -1.97; P < 0.001). Figure 1A; supplemental material available online with this article; doi:10.1172/JCI69094DS1). Gene set enrichment analysis (GSEA) showed a significantly different distribution of the STAT3 activation-associated genes among the hierarchical clustering-defined gene expression groups (normalized enrichment score [NES], -1.97; nominal P < 0.001; Figure 1G). In addition, mining the public repository Oncomine (www.oncomine. org) showed that STAT3 target genes were elevated in MM versus control tissue (Supplemental Figure 1B). Furthermore, we found the STAT3 signaling gene expression pattern to be associated with low bone disease, the MMSET groups, and the presence of a gain of the 1q21 locus, whereas we identified an inverse correlation with hyperdiploid disease (Supplemental Figure 1, C-E). Thus, STAT3 phosphorylation and target gene activation seems to be a major hallmark of a large subgroup of human MM. Constitutive GP130 signaling induces myeloma formation in a murine BM transduction-transplantation model. To test whether constitutive activation of GP130 signaling enables B cells to proliferate independently of cytokine stimulation, the IL-3-dependent Analysis of the malignant plasma cells revealed a t(12;15) translocation involving c-Myc (16). While Eμ-Myc transgenic mice (in which MYC expression is under control of the Eμ enhancer) develop aggressive pro-/pre-B cell lymphomas early in life (17), activationinduced deaminase-dependent expression of MYC in germinal center B cells leads to a high incidence of MM with a median survival of approximately 2 years (4). Transgenic mice expressing abnormally high levels of XBP-1, a protein involved in the terminal differentiation of B cells, develop monoclonal gammopathy of undetermined significance (MGUS), and some develop MM later in life (18). The Journal of Clinical Investigation R e s e a R c h a R t i c l e5In the present study, we showed that constitutive activation of GP130/JAK/STAT3 signal transduction in a retroviral murine BM transduction-transplantation model was sufficient to induce or facilitate MM development in mice. This model was characterized by very high penetrance and relatively short latency. Importantly, constitutive GP130 activation efficiently cooperated with MYC overexpression by driving cell growth and differentiation of malignant plasma cells. Our data indicate that constitutive GP130 signal transduction is a critical early step in myelomagenesis. Results STAT3 phosphorylation and target gene activation is a hallmark of human MM.Activation of the IL-6/IL-6R/GP130 complex is crucial for survival and proliferation of human myeloma (6,11,13), and the JAK/STAT3 pathway is a major target downstream of IL-6R/GP130 signaling (8,14). We therefore evaluated a series of BM biopsies from pati...

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Section: Stat3 Phosphorylation and Target Gene Activation Is A Hallmamentioning

confidence: 99%

“…Blocking IL-6 or IL-6R or inhibiting JAK/STAT3 results in growth arrest and apoptosis of MM cells. However, there is also evidence that IL-6 signaling might be dispensable for MM cell survival in the context of BM stromal cells (6,(11)(12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

GP130 activation induces myeloma and collaborates with MYC

Dechow¹,

Steidle²,

Götze³

et al. 2014

J. Clin. Invest.

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“…Leptin-induced HSC proliferation is related to the activation of JAK-STAT, MAPK and P13K/AKT and on the subsequent activation of signal transduction pathways [12,13]. JAK/STAT signaling is associated with physiological and pathological responses, involved in cell proliferation, differentiation, functioning and apoptosis, and is an important pathway mediating cytokine signal transduction [14,15].…”

Section: Discussionmentioning

confidence: 99%

Plumbagin Inhibits Leptin-Induced Proliferation of Hepatic Stellate Cells via JAK2-STAT3 Pathway to Protect against Hepatic Fibrosis

Wei¹,

Zhao²,

Zhang³

et al. 2013

Trop. J. Pharm Res

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“…Hence, this data suggest that JAK1 inhibition affects inflammatory processes. Additionally, in vitro studies revealed decreased tumor cell proliferation and activated apoptosis of glioblastoma cells and multiple myeloma cells following JAK1 inhibition [19,20] . However, further investigation is necessary to uncover the potential link between KRAS and JAK1 as well as the potential of JAK1 as a prognostic marker or a drug able target in PDAC.…”

Section: Articlesmentioning

confidence: 99%

Complexity of molecular alterations impacts pancreatic cancer prognosis

Regel

Kong²,

Bruns³

et al. 2013

WJGO

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Individualized cancer treatment (e.g. targeted therapy) based on molecular alterations has emerged as an important strategy to improve the current standard-of-care chemotherapy. A large number of studies have demonstrated the importance of biomarkers not only in predicting prognosis but more importantly in predicting the response towards therapies. For example, amplification or mutation status of the two biomarkers HER2 (human epidermal growth factor 2) and BRCA (breast cancer) can be used to decide on a specific targeted therapy in breast cancer. However, no biomarkers with a similar clinical impact have been identified in pancreatic ductal adenocarcinoma. Although many genome-wide and proteome-based high-throughput studies have identified candidate genes or proteins as promising biomarkers, none of them were eventually transferred into the clinical setting. Notably, the most reliable markers for predicting prognosis are still the tumor stage and grade and biomarkers for therapy response remain undefined. One reason lies in the lack of systemic approaches to analyze the complexity of dominating cancer pathways and the impact of such signal complexity on prognosis and therapy response

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The novel JAK inhibitor CYT387 suppresses multiple signalling pathways, prevents proliferation and induces apoptosis in phenotypically diverse myeloma cells

Cited by 75 publications

References 36 publications

GP130 activation induces myeloma and collaborates with MYC

GP130 activation induces myeloma and collaborates with MYC

Plumbagin Inhibits Leptin-Induced Proliferation of Hepatic Stellate Cells via JAK2-STAT3 Pathway to Protect against Hepatic Fibrosis

Complexity of molecular alterations impacts pancreatic cancer prognosis

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