Evidence of ABL-kinase domain mutations in highly purified primitive stem cell populations of patients with chronic myelogenous leukemia

Biochem Biophys Res Commun. 2004 Oct 22;323(3):728-30. doi: 10.1016/j.bbrc.2004.08.169.

Abstract

To study the hierarchical levels of stem cell targets for ABL-kinase domain mutations in CML, highly purified CD34+CD38- and CD34+CD38+ cell populations and their LTC-IC-derived progeny were analyzed in four patients at diagnosis (n=1) or in advanced phases (n=3) of their disease. In the single patient with early phase CML who later developed an Imatinib Mesylate-resistance and a Y253H mutation, no mutation was detectable in purified cell fractions analyzed at diagnosis nor in their LTC-IC-derived progeny. In contrast, in three patients in advanced phase CML, ABL-kinase mutations demonstrated in peripheral blood cells by sequencing (Q252E and M351T) were detectable in the FACS-sorted cells and became amplified in the LTC-IC-derived progeny of the primitive cells. These findings demonstrate that in late CP or advanced CML, ABL-kinase mutations occur as an intraclonal event in the primitive Ph1+ stem cell compartments with progression of this clone towards IM-resistant blast phase.

Publication types

  • Comparative Study
  • Evaluation Study

MeSH terms

  • Antineoplastic Agents / administration & dosage
  • Benzamides
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics
  • Cells, Cultured
  • Drug Resistance / genetics
  • Enzyme Inhibitors / administration & dosage
  • Fusion Proteins, bcr-abl / genetics*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Genetic Predisposition to Disease / genetics
  • Genetic Testing / methods
  • Humans
  • Imatinib Mesylate
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
  • Mutation
  • Phosphotransferases / antagonists & inhibitors
  • Phosphotransferases / genetics*
  • Piperazines / administration & dosage*
  • Protein Structure, Tertiary
  • Pyrimidines / administration & dosage*
  • Sequence Analysis, Protein
  • Stem Cells / drug effects*
  • Stem Cells / enzymology*
  • Stem Cells / pathology
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Benzamides
  • Enzyme Inhibitors
  • Piperazines
  • Pyrimidines
  • Imatinib Mesylate
  • Phosphotransferases
  • Fusion Proteins, bcr-abl