ASK1 promotes apoptosis of normal and malignant plasma cells

Fan Ru Lin, Shang Yi Huang, Kuo Hsuan Hung, Shin Tang Su, Cheng Han Chung, Atsushi Matsuzawa, Michael Hsiao, Hidenori Ichijo, Kuo I. Lin

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)

Abstract

Although the overproduction of immunoglobulins by short-lived plasma cells accompanying an immune response links with their apoptosis, how long-lived plasma cells adapt to ensure their longevity in this context is obscure. Here, we show that apoptosis signal-regulating kinase 1 (ASK1) contributes to apoptosis of plasma cells because ASK1 activity was induced during differentiation of short-lived plasma cells, and, when produced by ASK1-deficient mice, these cells survived better than those of control mice. Moreover, antigen-specific long-lived plasma cells generated by immunization accumulated in ASK1-deficient mice, suggesting ASK1 also plays a negative role in survival of long-lived plasma cells. In malignant plasma cells, ASK1 transcription was directly suppressed by B lymphocyte-induced maturation protein-1 (Blimp-1). The expression of ASK1 and Blimp-1 showed an inverse correlation between normal human mature B cells and bone marrow plasma cells from patients with multiple myeloma (MM). Suppression of ASK1 is crucial for cell survival because its enforced expression in MM cells caused apoptosis in vitro and lowered MM load in a xenograft animal model; furthermore, alteration of ASK1 activity affected MM cell survival. Our findings indicate a novel mechanism underlying the regulation of survival in normal and malignant plasma cells by ASK1.

Original languageEnglish
Pages (from-to)1039-1047
Number of pages9
JournalBlood
Volume120
Issue number5
DOIs
Publication statusPublished - 2012 Aug 2
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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