IL-6-independent expression of Mcl-1 in human multiple myeloma.
Mcl-1 is a critical antiapoptotic survival factor for human multiple myeloma (MM). We examined the importance of IL-6 for Mcl-1 expression in five MM cell lines and in primary MM cells from 14 patients. While culture of MM.1S cells in IL-6 did induce Mcl-1 expression, four other MM cell lines exhibited high levels of Mcl-1 expression that were unaffected by IL-6. Similarly, Mcl-1 expression in 10 of 14 primary MM isolates was found to be IL-6-independent. An analysis of the mechanisms responsible for IL-6-independent Mcl-1 expression was undertaken. ERK1/2 activity did not influence Mcl-1 expression, distinct from Mcl-1 regulation that occurs during myeloid differentiation from hematopoietic progenitor cells. Inhibition of the PI3K pathway led to growth inhibition of 8226 and ANBL-6 cells without reduction of Mcl-1 levels, and high level Mcl-1 expression was maintained in the absence of activated STAT3. Analysis of the transcriptional activity of 5'-regulatory sequences from the human Mcl-1 gene in MM cells demonstrated high levels of IL-6-independent indicator gene activation as predicted. These data demonstrate that the mechanisms regulating Mcl-1 levels in MM cells are heterogeneous, and are often independent from IL-6 signaling pathways.
Zhang
Bin
B
University of Maryland Greenebaum Cancer Center, Baltimore 21201, USA.
Potyagaylo
Valeria
V
Fenton
Robert G
RG
D001483:Base Sequence; D015153:Blotting, Western; D016895:Culture Media, Serum-Free; D017931:DNA Primers; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology*; D009101:Multiple Myeloma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases; D019253:Proto-Oncogene Proteins c-bcl-2; D012045:Regulatory Sequences, Nucleic Acid; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D016895:Culture Media, Serum-Free; D017931:DNA Primers; D015850:Interleukin-6; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019869:Phosphatidylinositol 3-Kinases