The level of TACI gene expression in myeloma cells is associated with a signature of microenvironment dependence versus a plasmablastic signature

Moreaux, Jérôme; Cremer, Friedrich W.; Rème, Thierry; Raab, Marc S.; Mahtouk, Karène; Kaukel, Philine; Pantesco, Véronique; Vos, John De; Jourdan, Éric; Jauch, Anna; Legouffe, Eric; Moos, Marion; Fiol, Geneviève; Goldschmidt, Hartmut; Rossi, Jean François; Hose, Dirk; Klein, Bernard

doi:10.1182/blood-2004-11-4512

Cited by 237 publications

(229 citation statements)

References 70 publications

Supporting

Mentioning

217

Contrasting

Unclassified

Order By: Relevance

“…22,23 Osteoclasts have been shown to express high levels of APRIL and BAFF and thus may represent an important paracrine source of these survival factors. 17 Here, for the first time we demonstrate the association between TACI gene expression by myeloma cells and their response to inhibitors of APRIL and BAFF in vivo and ex vivo.…”

Section: Introductionmentioning

confidence: 99%

“…14,16 Although myeloma cells can express very low levels of BAFF and APRIL, circulating levels of these cytokines in myeloma patients is higher than that in normal individuals, suggesting that BM microenvironmental cells are a major source of these factors in myeloma patients. 14,16 It has been shown that differences in TACI gene expression can distinguish tumors with a BM microenvironment-dependent signature (TACI high ) from those with a plasmablastic signature (TACI low ), 17 suggesting that TACI high myeloma cells may be more sensitive to growth factor withdrawal.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Atacicept (TACI-Ig) inhibits growth of TACIhigh primary myeloma cells in SCID-hu mice and in coculture with osteoclasts

Yaccoby

Pennisi

et al. 2007

Leukemia

View full text Add to dashboard Cite

APRIL (a proliferation-inducing Ligand) and BLyS/BAFF (B-lymphocyte stimulator/B-cell-activating factor of the TNF (tumor necrosis factor) family have been shown to be the survival factors for certain myeloma cells in vitro. BAFF binds to the TNF-related receptors such as B-cell maturation antigen (BCMA), transmembrane activator and CAML interactor (TACI) and BAFFR, whereas APRIL binds to TACI and BCMA and to heparan sulfate proteoglycans (HSPG) such as syndecan-1. TACI gene expression in myeloma reportedly can distinguish tumors with a signature of microenvironment dependence (TACI high ) versus a plasmablastic signature (TACI low ). We tested the effect of atacicept (formerly TACI-Ig, which blocks APRIL and BAFF) and BAFFR-Ig (which blocks BAFF only) on primary myeloma growth in the SCID-hu model and in coculture with osteoclasts. With only few exceptions, atacicept and to a lesser extent BAFFR-Ig, inhibited growth of TACI high but not TACI low myeloma samples in vivo and ex vivo, and the response rate was inversely correlated with TACI expression. Most TACI high myeloma cells were molecularly classified as being low risk with our recently described 70-gene model. APRIL and BAFF were highly expressed by osteoclasts and were upregulated in myeloma cells after coculture with osteoclasts. Our findings suggest that APRIL plays an essential role in the survival of TACI high bone marrow-dependent myeloma cells and TACI gene expression may be a useful predictive marker for patients who could benefit from atacicept treatment.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Atacicept (TACI-Ig) inhibits growth of TACIhigh primary myeloma cells in SCID-hu mice and in coculture with osteoclasts

Yaccoby

Pennisi

et al. 2007

Leukemia

View full text Add to dashboard Cite

show abstract

“…1,6-8 IL-6 is mainly produced by BMSCs, 1,6 whereas OCs are a major producer of BAFF and APRIL in the MM bone marrow microenvironment. 9,10 The serine/threonine kinase Pim-2 has been demonstrated to be transcriptionally upregulated to promote survival of hematopoietic cells in response to ambient growth factors and cytokines. 11 We demonstrate herein that Pim-2 is upregulated in MM cells by BMSCs and OCs, and acts as an important pro-survival mediator.…”

Section: Introductionmentioning

confidence: 99%

The serine/threonine kinase Pim-2 is a novel anti-apoptotic mediator in myeloma cells

et al. 2011

View full text Add to dashboard Cite

Bone marrow stromal cells (BMSCs) and osteoclasts (OCs) confer multiple myeloma (MM) cell survival through elaborating factors. We demonstrate herein that IL-6 and TNF family cytokines, TNFa, BAFF and APRIL, but not IGF-1 cooperatively enhance the expression of the serine/threonine kinase Pim-2 in MM cells. BMSCs and OCs upregulate Pim-2 expression in MM cells largely via the IL-6/STAT3 and NF-jB pathway, respectively. Pim-2 short interfering RNA reduces MM cell viability in cocultures with BMSCs or OCs. Thus, upregulation of Pim-2 appears to be a novel anti-apoptotic mechanism for MM cell survival. Interestingly, the mammalian target of rapamycin inhibitor rapamycin further suppresses the MM cell viability in combination with the Pim-2 silencing. The Pim inhibitor (Z)-5-(4-propoxybenzylidene) thiazolidine-2, 4-dione and the PI3K inhibitor LY294002 cooperatively enhance MM cell death. The Pim inhibitor suppresses 4E-BP1 phosphorylation along with the reduction of Mcl-1 and c-Myc. Pim-2 may therefore become a new target for MM treatment.

show abstract

“…Bone marrow plasma cells, 18 peripheral CD27 + memory B cells, 25 and polyclonal plasmablastic cells 26 were generated as described previously. The XG lines were generated at INSERM U847 as previously reported, [27][28][29] the human myeloma cell lines U266, RPMI-8226, LP-1, OPM-2, SK-MM-2, AMO-1, JJN-3, NCI-H929, KMS-12-BM, KMS-11, KMS-12-PE, KMS-18, MM1.S, JIM3, KARPAS-620, L363 and ANBL6 were purchased from the German Collection of Microorganisms and Cell Cultures (Braunschweig, Germany) and the American Type Cell Culture (Wesel, Germany), respectively, and cultured as recommended.…”

Section: Samplesmentioning

confidence: 99%

Proliferation is a central independent prognostic factor and target for personalized and risk-adapted treatment in multiple myeloma

Hose

Rème²,

Hielscher³

et al. 2010

Haematologica

192

196

View full text Add to dashboard Cite

BackgroundProliferation of malignant plasma cells is a strong adverse prognostic factor in multiple myeloma and simultaneously targetable by available (e.g. tubulin polymerase inhibitors) and upcoming (e.g. aurora kinase inhibitors) compounds. Design and MethodsWe assessed proliferation using gene expression-based indices in 757 samples including independent cohorts of 298 and 345 samples of CD138-purified myeloma cells from previously untreated patients undergoing high-dose chemotherapy, together with clinical prognostic factors, chromosomal aberrations, and gene expression-based high-risk scores. ResultsIn the two cohorts, 43.3% and 39.4% of the myeloma cell samples showed a proliferation index above the median plus three standard deviations of normal bone marrow plasma cells. Malignant plasma cells of patients in advanced stages or those harboring disease progressionassociated gain of 1q21 or deletion of 13q14.3 showed significantly higher proliferation indices; patients with gain of chromosome 9, 15 or 19 (hyperdiploid samples) had significantly lower proliferation indices. Proliferation correlated with the presence of chromosomal aberrations in metaphase cytogenetics. It was significantly predictive for event-free and overall survival in both cohorts, allowed highly predictive risk stratification (e.g. event-free survival 12.7 versus 26.2 versus 40.6 months, P<0.001) of patients, and was largely independent of clinical prognostic factors, e.g. serum β2-microglobulin, International Staging System stage, associated high-risk chromosomal aberrations, e.g. translocation t(4;14), and gene expression-based high-risk scores. ConclusionsProliferation assessed by gene expression profiling, being independent of serum-β2-microglobulin, International Staging System stage, t(4;14), and gene expression-based risk scores, is a central prognostic factor in multiple myeloma. Surrogating a biological targetable variable, gene expression-based assessment of proliferation allows selection of patients for riskadapted anti-proliferative treatment on the background of conventional and gene expressionbased risk factors.

show abstract

The level of TACI gene expression in myeloma cells is associated with a signature of microenvironment dependence versus a plasmablastic signature

Cited by 237 publications

References 70 publications

Atacicept (TACI-Ig) inhibits growth of TACIhigh primary myeloma cells in SCID-hu mice and in coculture with osteoclasts

Atacicept (TACI-Ig) inhibits growth of TACIhigh primary myeloma cells in SCID-hu mice and in coculture with osteoclasts

The serine/threonine kinase Pim-2 is a novel anti-apoptotic mediator in myeloma cells

Proliferation is a central independent prognostic factor and target for personalized and risk-adapted treatment in multiple myeloma

Contact Info

Product

Resources

About