BAFF and APRIL as osteoclast-derived survival factors for myeloma cells: a rationale for TACI-Fc treatment in patients with multiple myeloma

Abe, Masahiro; Kido, Shinsuke; Hiasa, Masahiro; Nakano, Ayako; Oda, Asuka; Amou, Hiroe; Matsumoto, Toshio

doi:10.1038/sj.leu.2404228

Cited by 100 publications

(77 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Discussion APRIL and BAFF have been shown to be upregulated in the myeloma microenvironment, stimulate survival and proliferation of myeloma cells in vitro through autocrine and paracrine mechanisms and protect tumor cells from drug-induced apoptosis. [15][16][17][18]33 In this study, we demonstrated that osteoclasts express high levels of APRIL and BAFF and that these cytokines are upregulated by myeloma cells after coculture with osteoclasts. Atacicept effectively reduced the growth of TACI high primary myeloma cells in SCID-hu mice and in long-term coculture with the supportive osteoclasts.…”

Section: Antimyeloma Response Of Atacicept and Baffr-ig In Scid-hu Micementioning

confidence: 83%

“…Atacicept-inhibited survival of myeloma cells by 435% in three of six experiments (Table 1; Po0.03). 18 As in the SCID-hu mice, the antimyeloma effect of atacicept was evident on TACI high but not TACI low cases and, as in the in vivo experiments, was inversely correlated with TACI expression level (r ¼ À0.9, Po0.01; Table 1; Figure 5a). For the three TACI high myeloma samples, atacicept-inhibited myeloma cell survival in a doserelated manner (Figure 5b).…”

Section: Antimyeloma Response Of Atacicept and Baffr-ig In Scid-hu Micementioning

confidence: 84%

“…14 In coculture of certain myeloma cell lines with the supporting osteoclasts or dendritic cells, TACI-Ig addition resulted in reduced myeloma cell growth and diminished clonogenic potential. 18,19 In the current study, we further tested the involvement of APRIL and BAFF in myeloma pathogenesis using two inhibitorsFatacicept (TACI-Ig) and BAFFR-IgFin our in vivo 20,21 and ex vivo 22,23 experimental systems for primary myeloma. Whereas atacicept binds and neutralizes both BAFF and APRIL, BAFFR-Ig blocks only BAFF y.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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: Antimyeloma Response Of Atacicept and Baffr-ig In Scid-hu Micementioning

confidence: 83%

Section: Antimyeloma Response Of Atacicept and Baffr-ig In Scid-hu Micementioning

confidence: 84%

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

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

Self Cite

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

“…Besides releasing immobilized growth factors from the bone matrix, osteoclasts secrete several factors that support myeloma cells, including IL-6 (the most important growth factor for multiple myeloma cells), 28 annexin II (AXII), 29 osteopontin, 30 fibroblast activation protein, 31 BAFF (B-cell-activating factor belonging to the TNF family) and APRIL (a proliferation-inducing ligand). 32 Figure 1a summarizes these interactions.…”

Section: Factors Driving Osteoclast Formation and Activity In Mmbdmentioning

confidence: 99%

Mechanisms of multiple myeloma bone disease

Galson¹,

Silbermann²,

Roodman³

2012

BoneKEy Reports

View full text Add to dashboard Cite

Multiple myeloma is the second most common hematological malignancy and the most frequent cancer to involve the skeleton. Multiple myeloma bone disease (MMBD) is characterized by abnormal bone remodeling with dysfunction of both bone resorption and bone formation, and thus can be used as a paradigm for other inflammatory bone diseases, and the regulation of osteoclasts and osteoblasts in malignancy. Studies of MMBD have identified novel regulators that increase osteoclastogenesis and osteoclast function, repress osteoblast differentiation, increase angiogenesis, or permanently alter stromal cells. This review will discuss the current understanding of mechanisms of osteoclast and osteoblast regulation in MMBD, and therapeutic approaches currently in use and under development that target mediators of bone destruction and blockade of bone formation for myeloma patients, including new anabolic therapies.

show abstract

BAFF and APRIL as osteoclast-derived survival factors for myeloma cells: a rationale for TACI-Fc treatment in patients with multiple myeloma

Cited by 100 publications

References 6 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

Mechanisms of multiple myeloma bone disease

Contact Info

Product

Resources

About