High Mda-7 expression promotes malignant cell survival and p38 MAP kinase activation in chronic lymphocytic leukemia

Leukemia. 2006 Mar;20(3):498-504. doi: 10.1038/sj.leu.2404073.


Chronic lymphocytic leukemia (CLL)-B-cells are quiescent differentiated cells that produce interleukin (IL)-10 and accumulate due to resistance to apoptosis. The mechanisms underlying such resistance are poorly understood. Herein we show that all CLL B-cells tested (30/30) display high mRNA and protein expression of the tumor suppressor Mda-7/IL-24, an IL-10 family member, in comparison to normal B cells. A downstream Mda-7 signaling target, p38 mitogen-activated protein kinase (MAPK) was highly phosphorylated in all CLL cells but not in normal B-cells. Mda-7 expression and p38 MAPK phosphorylation diminished in culture and the latter could be reinduced by recombinant (r)-IL-24 or LPS and Mda-7 transfection. Mda-7/IL-24 siRNA specifically inhibited p38 MAPK phosphorylation in CLL without affecting p38 MAPK, bcl2, or Lyn expression, further demonstrating the direct role of Mda-7/IL-24 in p38 MAPK activation. Both pharmacological inhibition of p38 MAPK and Mda-7 silencing augmented spontaneous apoptosis by three-fold in CLL cells cultured in autologous serum, which was reversed by LPS and r-IL-24. We established the role of p38 MAPK in CLL cell survival and demonstrated a paradoxical effect, whereby Mda-7 and IL-24, inducers of apoptosis in diverse cancer cells, promote the survival of CLL B-cells through p38 MAPK activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Base Sequence
  • Cell Survival / drug effects
  • Cell Survival / genetics*
  • DNA Primers
  • Enzyme Activation
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Glycosylation
  • Humans
  • Interleukins / genetics
  • Interleukins / metabolism*
  • Interleukins / pharmacology
  • Leukemia, Lymphocytic, Chronic, B-Cell / enzymology*
  • Male
  • Middle Aged
  • Phosphorylation
  • RNA Interference
  • RNA, Messenger / genetics
  • Recombinant Proteins / pharmacology
  • Reverse Transcriptase Polymerase Chain Reaction
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • DNA Primers
  • Interleukins
  • RNA, Messenger
  • Recombinant Proteins
  • interleukin-24
  • p38 Mitogen-Activated Protein Kinases