Interleukin-6–dependent gene expression profiles in multiple myeloma INA-6 cells reveal a Bcl-2 family–independent survival pathway closely associated with Stat3 activation

Brocke-Heidrich, Katja; Kretzschmar, A.; Pfeifer, Gabriele; Henze, Christian; Löffler, Dennis; Koczan, Dirk; Thiesen, Hans‐Jürgen; Burger, Renate; Gramatzki, Martin; Horn, Friedemann

doi:10.1182/blood-2003-04-1048

Cited by 133 publications

(126 citation statements)

References 76 publications

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“…In a previous study, we identified the proto-oncogene BCL3 as an IL-6 target gene (Brocke-Heidrich et al, 2004). Here, we show that IL-6 induces BCL3 expression in myeloma cells but not in hepatocellular carcinoma cells.…”

Section: Discussionsupporting

confidence: 47%

“…When comparing the gene expression profiles of INA-6 cells grown in the presence or absence of IL-6, we observed the induction of BCL3 (Brocke-Heidrich et al, 2004), originally identified as a candidate protooncogene overexpressed in certain cases of B-cell chronic lymphocytic leukemia as a consequence of a t(14;19) chromosomal translocation Ohno et al, 1990). High BCL3 expression has also been reported in a subgroup of anaplastic large-cell lymphoma (Nishikori et al, 2003).…”

Section: Introductionmentioning

confidence: 75%

“…Among the IL-6 target genes potentially involved in the pathogenesis of MM identified by microarray analysis of INA-6 cells was the BCL3 gene (Brocke-Heidrich et al, 2004), whose induction was confirmed by real-time PCR at different time points upon IL-6 treatment ( Figure 1a).…”

Section: Bcl3 Expression Is Induced By Il-6 In MM Cell Linesmentioning

confidence: 85%

“…Interleukin (IL)-6 is known to play an essential role in the proliferation and survival of MM cells (Klein et al, 1995). In the human IL-6-dependent MM cell line INA-6 (Burger et al, 2001), we recently demonstrated that IL-6 promotes survival through an as yet unknown antiapoptotic pathway that required the activation of signal transducer and activator of transcription 3 (Stat3) (Brocke-Heidrich et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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BCL3 is induced by IL-6 via Stat3 binding to intronic enhancer HS4 and represses its own transcription

Brocke-Heidrich

Cvijic

et al. 2006

Oncogene

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BCL3 is a proto-oncogene affected by chromosomal translocations in some patients with chronic lymphocytic leukemia. It is an IjB family protein that is involved in transcriptional regulation of a number of NF-jB target genes. In this study, interleukin (IL)-6-induced BCL3 expression and its effect on survival of multiple myeloma (MM) cells were examined. We demonstrate the upregulation of BCL3 by IL-6 in INA-6 and other MM cell lines. Sequence analysis of the BCL3 gene locus revealed four potential signal transducer and activator of transcription (Stat) binding sites within two conserved intronic enhancers regions: one located within enhancer HS3 and three within HS4. Chromatin immunoprecipitation experiments showed increased Stat3 binding to both enhancers upon IL-6 stimulation. Silencing Stat3 expression by small interfering RNA (siRNA) abrogated BCL3 expression by IL-6. Using reporter gene assays, we demonstrate that BCL3 transcription depends on HS4. Mutation of the Stat motifs within HS4 abolished IL-6-dependent BCL3 induction. Furthermore, BCL3 transcription was inhibited by its own gene product. This repressive feedback is mediated by NF-jB sites within the promoter and HS3. Finally, we show that overexpression of BCL3 increases apoptosis, whereas BCL3-specific siRNA does not affect the viability of INA-6 cells suggesting that BCL3 is not essential for the survival of these cells.

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Section: Discussionsupporting

confidence: 47%

Section: Introductionmentioning

confidence: 75%

Section: Bcl3 Expression Is Induced By Il-6 In MM Cell Linesmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

BCL3 is induced by IL-6 via Stat3 binding to intronic enhancer HS4 and represses its own transcription

Brocke-Heidrich

Cvijic

et al. 2006

Oncogene

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“…Although the pathogenesis of the disease still remains unclear, it is well established that interleukin-6 (IL-6) plays an essential role in the malignant progression of MM [2][3]. Numerous reports suggest that IL-6 promotes survival and proliferation of MM cells through the phosphorylation of a cell signaling protein, Stat3 [4][5]. The Stat proteins are a conserved family of transcription factors implicated in regulating processes such as inflammation, survival, proliferation, metastasis, angiogenesis, and chemoresistance of tumor cells [6].…”

Section: Introductionmentioning

confidence: 99%

QUICK identification and SPR validation of signal transducers and activators of transcription 3 (Stat3) interacting proteins

Zheng

Zhong

Xiong

et al. 2012

Journal of Proteomics

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Role of Bruton's tyrosine kinase in myeloma cell migration and induction of bone disease

et al. 2013

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Myeloma cells typically grow in bone, recruit osteoclast precursors and induce their differentiation and activity in areas adjacent to tumor foci. Bruton’s tyrosine kinase (BTK), of the TEC family, is expressed in hematopoietic cells and is particularly involved in B-lymphocyte function and osteoclastogenesis. We demonstrated BTK expression in clinical myeloma plasma cells, interleukin (IL) –6– or stroma–dependent cell lines and osteoclasts. SDF-1 induced BTK activation in myeloma cells and BTK inhibition by small hairpin RNA or the small molecule inhibitor, LFM-A13, reduced their migration toward stromal cell-derived factor-1 (SDF-1). Pretreatment with LFM-A13 also reduced in vivo homing of myeloma cells to bone using bioluminescence imaging in the SCID-rab model. Enforced expression of BTK in myeloma cell line enhanced cell migration toward SDF-1 but had no effect on short-term growth. BTK expression was correlated with cell-surface CXCR4 expression in myeloma cells (n = 33, r = 0.81, P < 0.0001), and BTK gene and protein expression was more profound in cell-surface CXCR4-expressing myeloma cells. BTK was not upregulated by IL-6 while its inhibition had no effect on IL-6 signaling in myeloma cells. Human osteoclast precursors also expressed BTK and cell-surface CXCR4 and migrated toward SDF-1. LFM-A13 suppressed migration and differentiation of osteoclast precursors as well as bone-resorbing activity of mature osteoclasts. In primary myeloma-bearing SCID-rab mice, LFM-A13 inhibited osteoclast activity, prevented myeloma-induced bone resorption and moderately suppressed myeloma growth. These data demonstrate BTK and cell-surface CXCR4 association in myeloma cells and that BTK plays a role in myeloma cell homing to bone and myeloma-induced bone disease.

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Interleukin-6–dependent gene expression profiles in multiple myeloma INA-6 cells reveal a Bcl-2 family–independent survival pathway closely associated with Stat3 activation

Abstract: Interleukin 6 (IL-6) is a growth and survival factor for multiple myeloma cells. As we report here, the IL-6-dependent human myeloma cell line INA-6 responds with a remarkably rapid and complete apoptosis to cytokine withdrawal.

Cited by 133 publications

References 76 publications

BCL3 is induced by IL-6 via Stat3 binding to intronic enhancer HS4 and represses its own transcription

BCL3 is induced by IL-6 via Stat3 binding to intronic enhancer HS4 and represses its own transcription

QUICK identification and SPR validation of signal transducers and activators of transcription 3 (Stat3) interacting proteins

Role of Bruton's tyrosine kinase in myeloma cell migration and induction of bone disease

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