IL-6-independent expression of Mcl-1 in human multiple myeloma

Oncogene. 2003 Mar 27;22(12):1848-59. doi: 10.1038/sj.onc.1206358.

Abstract

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.

MeSH terms

  • Base Sequence
  • Blotting, Western
  • Culture Media, Serum-Free
  • DNA Primers
  • Gene Expression Regulation, Neoplastic / physiology*
  • Humans
  • Interleukin-6 / physiology*
  • Multiple Myeloma / enzymology
  • Multiple Myeloma / genetics*
  • Multiple Myeloma / pathology
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins / genetics*
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-bcl-2*
  • Regulatory Sequences, Nucleic Acid
  • Transcriptional Activation
  • Tumor Cells, Cultured

Substances

  • Culture Media, Serum-Free
  • DNA Primers
  • Interleukin-6
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Phosphatidylinositol 3-Kinases