ASK1 promotes apoptosis of normal and malignant plasma cells.
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.
Genomics Research Center, Academia Sinica, Taipei, Taiwan.
Fan-Ru
FR
Lin
Shang-Yi
SY
Huang
Kuo-Hsuan
KH
Hung
Shin-Tang
ST
Su
Cheng-Han
CH
Chung
Atsushi
A
Matsuzawa
Michael
M
Hsiao
Hidenori
H
Ichijo
Kuo-I
KI
Lin
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D006801:Humans; D007958:Leukocyte Count; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D054219:Neoplasms, Plasma Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010950:Plasma Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human