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Myeloma

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

Leukemia volume 22, pages 406–413 (2008)Cite this article

Abstract

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 (TACIhigh) versus a plasmablastic signature (TACIlow). 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 TACIhigh but not TACIlow myeloma samples in vivo and ex vivo, and the response rate was inversely correlated with TACI expression. Most TACIhigh 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 TACIhigh bone marrow-dependent myeloma cells and TACI gene expression may be a useful predictive marker for patients who could benefit from atacicept treatment.

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Acknowledgements

This work was supported by Grants CA-93897 (SY), CA55819 (BB and JS), and CA97513 (JS) from the National Cancer Institute, by Senior and Translational Research Awards from the Multiple Myeloma Research Foundation (SY) and by a grant from ZymoGenetics Inc. and Merck-Serono International, SA (JS and SY). SY performed research, analyzed and interpreted data, and wrote the paper. AP and XL performed research experiments. SRD provided materials, analyzed and interpreted data. FZ analyzed all microarray data. BB contributed resources including patient material and clinical data. JS conceptualized the work, analyzed and interpreted data. We recognize the efforts of the members of Dr Yaccoby's laboratory; Rinku Saha, Wen Ling and Paul Perkins, and Derek Janszen (ZymoGenetics Inc.) for his assistance with the statistical analysis. We also thank the faculty, staff and patients of the Myeloma Institute for Research and Therapy for their support.

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Authors and Affiliations

  1. Department of Internal Medicine, Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    S Yaccoby, A Pennisi, X Li, F Zhan, B Barlogie & J D Shaughnessy Jr

  2. ZymoGenetics Inc., Seattle, WA, USA

    S R Dillon

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  1. S Yaccoby
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Correspondence to S Yaccoby.

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Yaccoby, S., Pennisi, A., Li, X. et al. Atacicept (TACI-Ig) inhibits growth of TACIhigh primary myeloma cells in SCID-hu mice and in coculture with osteoclasts. Leukemia 22, 406–413 (2008). https://doi.org/10.1038/sj.leu.2405048

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