Tumour necrosis factor-induced gene expression in human marrow stroma: clues to the pathophysiology of MDS?
Aberrant regulation of the tumour necrosis factor alpha gene (TNF) and stroma-derived signals are involved in the pathophysiology of myelodysplasia. Therefore, KG1a, a myeloid leukaemia cell line, was exposed to Tnf in the absence or presence of either HS-5 or HS-27a cells, two human stroma cell lines. While KG1a cells were resistant to Tnf-induced apoptosis in the absence of stroma cells, Tnf-promoted apoptosis of KG1a cells in co-culture experiments with stroma cells. To investigate the Tnf-induced signals from the stroma cells, we examined expression changes in HS-5 and HS-27a cells after Tnf exposure. DNA microarray studies found both discordant and concordant Tnf-induced expression responses in the two stroma cell lines. Tnf promoted an increased mRNA expression of pro-inflammatory cytokines [e.g. interleukin (IL)6, IL8 and IL32]. At the same time, Tnf decreased the mRNA expression of anti-apoptotic genes (e.g. BCL2L1) and increased the mRNA expression of pro-apoptotic genes (e.g. BID). Overall, the results suggested that Tnf induced a complex set of pro-inflammatory and pro-apoptotic signals in stroma cells that promote apoptosis in malignant myeloid clones. Additional studies will be required to determine which of these signals are critical for the induction of apoptosis in the malignant clones. Those insights, in turn, may point the way to novel therapeutic approaches.
Stirewalt
Derek L
DL
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. dstirewa@fhcrc.org
Mhyre
Andrew J
AJ
Marcondes
Mario
M
Pogosova-Agadjanyan
Era
E
Abbasi
Nissa
N
Radich
Jerald P
JP
Deeg
H Joachim
HJ
D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D009190:Myelodysplastic Syndromes / Q000503:physiopathology*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000187:drug effects* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; D018836:Inflammation Mediators; D014409:Tumor Necrosis Factor-alpha