Role of protein kinase C-delta (PKC-delta) in the generation of the effects of IFN-alpha in chronic myelogenous leukemia cells

Exp Hematol. 2005 May;33(5):550-7. doi: 10.1016/j.exphem.2005.01.014.


Objective: The mechanisms by which interferon alpha (IFN-alpha) induces antileukemic responses in chronic myelogenous leukemia (CML) cells are not known. We examined whether a member of the protein kinase C (PKC) family of proteins, PKC-delta, is activated during treatment of BCR-ABL cells with IFN-alpha and participates in the induction of interferon responses.

Methods: Immunoblots and immune complex kinase assays were performed to study the phosphorylation and activation of PKC-delta in response to IFN-alpha in CML-derived cell lines. The effects of pharmacological inhibition of PKC-delta on the suppressive effects of IFN-alpha on leukemic CFU-GM progenitors from CML patients were assessed by clonogenic assays in methylcellulose.

Results: IFN-alpha treatment of the sensitive CML-derived KT-1 cell line resulted in phosphorylation of PKC-delta and activation of its kinase domain. Such phosphorylation/activation of PKC-delta was required for phosphorylation of Stat1 on serine 727, as inhibition of PKC-delta activity blocked the IFN-alpha-dependent serine phosphorylation of Stat1 and IFN-alpha-inducible gene transcription. IFN-alpha treatment strongly inhibited leukemic CFU-GM progenitor colony formation from bone marrow or peripheral blood of patients with CML, and such inhibition was reversed by concomitant treatment of the cells with the PKC-delta pharmacologic inhibitor rottlerin.

Conclusion: Taken altogether, our data demonstrate that PKC-delta plays a critical role in Type I IFN signaling in BCR-ABL expressing cells, acting as a serine kinase for Stat1, to regulate transcriptional activation of interferon-regulated genes and induction of antileukemic responses.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cell Line, Tumor
  • DNA-Binding Proteins / metabolism
  • Enzyme Activation
  • Humans
  • Immunoprecipitation
  • Interferon-alpha / pharmacology*
  • Interferon-alpha / therapeutic use
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology*
  • Phosphorylation
  • Protein Kinase C / metabolism*
  • Protein Kinase C-delta
  • STAT1 Transcription Factor
  • Serine / metabolism
  • Trans-Activators / metabolism


  • DNA-Binding Proteins
  • Interferon-alpha
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Trans-Activators
  • Serine
  • PRKCD protein, human
  • Protein Kinase C
  • Protein Kinase C-delta