Abstract
The PML-RAR alpha fusion protein is central to the pathogenesis of acute promyelocytic leukemia (APL). Expression of this protein in transgenic mice initiates myeloid leukemias with features of human APL, but only after a long latency (8.5 months in MRP8 PML-RARA mice). Thus, additional changes contribute to leukemic transformation. Activating mutations of the FLT3 receptor tyrosine kinase are common in human acute myeloid leukemias and are frequent in human APL. To assess how activating mutations of FLT3 contribute to APL pathogenesis and impact therapy, we used retroviral transduction to introduce an activated allele of FLT3 into control and MRP8 PML-RARA transgenic bone marrow. Activated FLT3 cooperated with PML-RAR alpha to induce leukemias in 62 to 299 days (median latency, 105 days). In contrast to the leukemias that arose spontaneously in MRP8 PML-RARA mice, the activated FLT3/PML-RAR alpha leukemias were characterized by leukocytosis, similar to human APL with FLT3 mutations. Cytogenetic analysis revealed clonal karyotypic abnormalities, which may contribute to pathogenesis or progression. SU11657, a selective, oral, multitargeted tyrosine kinase inhibitor that targets FLT3, cooperated with all-trans retinoic acid to rapidly cause regression of leukemia. Our results suggest that the acquisition of FLT3 mutations by cells with a pre-existing t(15;17) is a frequent pathway to the development of APL. Our findings also indicate that APL patients with FLT3 mutations may benefit from combination therapy with all-trans retinoic acid plus an FLT3 inhibitor.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Administration, Oral
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Animals
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Antineoplastic Agents / pharmacology*
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
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Chromosome Aberrations
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Clone Cells / ultrastructure
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Drug Implants
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Drug Screening Assays, Antitumor
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Enzyme Inhibitors / administration & dosage
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Enzyme Inhibitors / pharmacology*
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Humans
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Leukemia, Promyelocytic, Acute / drug therapy*
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Leukemia, Promyelocytic, Acute / genetics
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Mice
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Mice, Transgenic
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Oncogene Proteins, Fusion / genetics
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Organic Chemicals / administration & dosage
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Organic Chemicals / pharmacology*
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Organic Chemicals / therapeutic use
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Phosphorylation / drug effects
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Protein Processing, Post-Translational / drug effects
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins / metabolism
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Radiation Chimera
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
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Receptor Protein-Tyrosine Kinases / genetics*
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Receptor Protein-Tyrosine Kinases / metabolism
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Tretinoin / administration & dosage
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Tretinoin / pharmacology*
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Tumor Cells, Cultured / drug effects
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Tumor Cells, Cultured / metabolism
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fms-Like Tyrosine Kinase 3
Substances
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Antineoplastic Agents
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Drug Implants
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Enzyme Inhibitors
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Neoplasm Proteins
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Oncogene Proteins, Fusion
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Organic Chemicals
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Proto-Oncogene Proteins
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SU 11657
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promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein
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Tretinoin
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FLT3 protein, human
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Flt3 protein, mouse
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Receptor Protein-Tyrosine Kinases
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fms-Like Tyrosine Kinase 3