A diphtheria toxin interleukin-3 fusion protein synergizes with tyrosine kinase inhibitors in killing leukemic progenitors from BCR/ABL positive acute leukemia

Leuk Res. 2010 Aug;34(8):1035-42. doi: 10.1016/j.leukres.2009.12.008.

Abstract

Despite initial remissions, most patients with Ph chromosome positive (Ph(+)) acute leukemia (AL) become refractory to tyrosine kinase inhibitors (TKIs) such as imatinib and dasatinib. This study was designed to determine if targeting the interleukin-3 receptor (IL-3R) with a diphtheria toxin fusion protein (DT(388)IL3) would improve the effectiveness of TKIs against Ph(+) AL cells. IL-3R subunits were detected on most Ph(+) cells and the IC50 for killing of colony forming cell (CFC) with DT(388)IL3 correlated with the level of IL-3Ralpha subunit by FACS. DT(388)IL3 synergized with both imatinib and dasatinib for killing of malignant CFCs. Long-term suspension culture-initiating cells (SC-ICs) and quiescent leukemic cells (G(0) in cell cycle) also were studied and synergistic interactions were again demonstrated. Thus, cotreatment with TKIs and DT(388)IL3 is much more effective in eliminating Ph(+) leukemic progenitors that express IL-3R than either agent alone.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Benzamides
  • Blotting, Western
  • Cell Cycle
  • Cell Proliferation
  • Cells, Cultured
  • Dasatinib
  • Diphtheria Toxin / therapeutic use*
  • Drug Synergism
  • Female
  • Flow Cytometry
  • Fusion Proteins, bcr-abl / genetics*
  • Fusion Proteins, bcr-abl / metabolism
  • Humans
  • Imatinib Mesylate
  • Interleukin-3 / therapeutic use*
  • Interleukin-3 Receptor alpha Subunit / genetics
  • Interleukin-3 Receptor alpha Subunit / metabolism
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / pathology
  • Male
  • Middle Aged
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / pathology
  • Piperazines / therapeutic use
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Pyrimidines / therapeutic use
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Recombinant Fusion Proteins / therapeutic use*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Thiazoles / therapeutic use

Substances

  • Benzamides
  • Diphtheria Toxin
  • IL3RA protein, human
  • Interleukin-3
  • Interleukin-3 Receptor alpha Subunit
  • Piperazines
  • Pyrimidines
  • RNA, Messenger
  • Recombinant Fusion Proteins
  • Thiazoles
  • diphtheria toxin-interleukin-3 fusion protein, recombinant
  • Imatinib Mesylate
  • Protein-Tyrosine Kinases
  • Fusion Proteins, bcr-abl
  • Dasatinib