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.
Copyright (c) 2010 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Aged
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Benzamides
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Blotting, Western
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Cell Cycle
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Cell Proliferation
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Cells, Cultured
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Dasatinib
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Diphtheria Toxin / therapeutic use*
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Drug Synergism
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Female
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Flow Cytometry
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Fusion Proteins, bcr-abl / genetics*
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Fusion Proteins, bcr-abl / metabolism
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Humans
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Imatinib Mesylate
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Interleukin-3 / therapeutic use*
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Interleukin-3 Receptor alpha Subunit / genetics
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Interleukin-3 Receptor alpha Subunit / metabolism
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Leukemia, Myeloid, Acute / drug therapy*
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Leukemia, Myeloid, Acute / metabolism
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Leukemia, Myeloid, Acute / pathology
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Male
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Middle Aged
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Neoplastic Stem Cells / drug effects*
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Neoplastic Stem Cells / pathology
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Piperazines / therapeutic use
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Pyrimidines / therapeutic use
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Recombinant Fusion Proteins / therapeutic use*
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Reverse Transcriptase Polymerase Chain Reaction
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Thiazoles / therapeutic use
Substances
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Benzamides
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Diphtheria Toxin
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IL3RA protein, human
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Interleukin-3
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Interleukin-3 Receptor alpha Subunit
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Piperazines
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Pyrimidines
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RNA, Messenger
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Recombinant Fusion Proteins
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Thiazoles
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diphtheria toxin-interleukin-3 fusion protein, recombinant
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Imatinib Mesylate
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Protein-Tyrosine Kinases
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Fusion Proteins, bcr-abl
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Dasatinib