Phosphorylation of spleen tyrosine kinase at tyrosine 348 (pSyk³⁴⁸) may be a marker of advanced phase of Chronic Myeloid Leukemia (CML)

Leuk Res. 2015 Mar;39(3):329-34. doi: 10.1016/j.leukres.2014.11.014. Epub 2014 Dec 13.

Abstract

We investigated Syk as a potential marker of CML progression. We observed a significant over-expression of Syk mRNA and constitutive phosphorylation of Syk Y348 in blast cells from six AP or BP-CML, but not in 15 CML in chronic phase. We could follow in vivo the recurrence of pSyk(348) throughout blast cell escape, despite observing storage of dasatinib in blast cells. A combination of dasatinib and R406 did not improve therapeutic efficacy in vitro. Our results strongly suggest that Syk activation could be a relevant biomarker of disease progression and dasatinib resistance but is probably not a molecular target.

Keywords: Chronic Myeloid Leukemia (CML); Dasatinib; Flow cytometry; Spleen tyrosine kinase (Syk); pSyk(348).

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols
  • Biomarkers, Tumor
  • Blast Crisis*
  • Child
  • Chronic Disease
  • Dasatinib
  • Disease Progression
  • Female
  • Flow Cytometry
  • Follow-Up Studies
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / mortality
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
  • Male
  • Middle Aged
  • Oxazines / pharmacology
  • Phosphorylation
  • Prognosis
  • Protein Kinase Inhibitors / pharmacology
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Pyridines / pharmacology
  • Pyrimidines / pharmacology
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Survival Rate
  • Syk Kinase
  • Thiazoles / pharmacology
  • Tumor Cells, Cultured
  • Young Adult

Substances

  • Biomarkers, Tumor
  • Intracellular Signaling Peptides and Proteins
  • N4-(2,2-dimethyl-3-oxo-4H-pyrid(1,4)oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine
  • Oxazines
  • Protein Kinase Inhibitors
  • Pyridines
  • Pyrimidines
  • RNA, Messenger
  • Thiazoles
  • Protein-Tyrosine Kinases
  • SYK protein, human
  • Syk Kinase
  • Dasatinib