Poor cytokine-induced phosphorylation in chronic myeloid leukemia patients at diagnosis is effectively reversed by tyrosine kinase inhibitor therapy

Exp Hematol. 2011 Jan;39(1):102-113.e1. doi: 10.1016/j.exphem.2010.09.005. Epub 2010 Oct 12.


Objective: In chronic myeloid leukemia (CML), uncontrolled tyrosine kinase activity of the BCR-ABL1 oncoprotein results in aberrant signaling pathways and increased cell proliferation. Acquired immune tolerance to leukemic antigens further enables tumor cell expansion. Tyrosine kinase inhibitor (TKI) therapy interferes with the immunoregulatory system by targeting off-target kinases both in malignant and nonmalignant cells. The aim of this study was to analyze the immune cell function by phosphoprotein profiling in CML patients.

Materials and methods: Blood samples from diagnostic phase and TKI-treated patients were analyzed by multicolor phosphoprotein flow cytometry enabling measurements at the single-cell level. Both unstimulated baseline activation status and cytokine-induced responses were evaluated.

Results: In diagnostic-phase and imatinib-treated patients, the baseline phosphoprotein activation status was similar to healthy controls. In dasatinib-treated patients, basal phosphoprotein levels were slightly decreased; in particular, the signal transduction and activator of transcription protein 3 pathway was affected in both myeloid and lymphoid cells. The activation responses to various cytokines, granulocyte-macrophage colony-stimulating factor in particular were significantly suppressed in untreated CML patients. During imatinib and dasatinib therapy, the aberrantly suppressed phosphorylation responses were normalized.

Conclusions: Cytokine responses are hampered in untreated CML patients, which may have an effect on various immunological processes in vivo. Interestingly, during TKI treatment, phosphorylation responses were normal, suggesting that TKI treatment does not alter the reactivity of healthy immune effector cells. However, dasatinib treatment was associated with diminished basal activation of the immunosuppressive signal transduction and activator of transcription protein 3 signaling pathway, which could have clinical significance in reversing the lymphocyte anergy against tumor cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents / therapeutic use*
  • Case-Control Studies
  • Cytokines / metabolism*
  • Female
  • Flow Cytometry
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / diagnosis
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
  • Male
  • Middle Aged
  • Phosphorylation
  • Protein Kinase Inhibitors / therapeutic use*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*


  • Antineoplastic Agents
  • Cytokines
  • Protein Kinase Inhibitors
  • Protein-Tyrosine Kinases