Abstract
Internal tandem duplication (ITD) mutations within the FMS-like tyrosine kinase-3 (FLT3) render the receptor constitutively active driving proliferation and survival in leukemic blasts. Expression of FLT3-ITD from the endogenous promoter in a murine knockin model results in progenitor expansion and a myeloproliferative neoplasm. In this study, we show that this expansion begins with overproliferation within a compartment of normally quiescent long-term hematopoietic stem cells (LT-HSCs), which become rapidly depleted. This depletion is reversible upon treatment with the small molecule inhibitor Sorafenib, which also ablates the disease. Although the normal LT-HSC has been defined as FLT3(-) by flow cytometric detection, we demonstrate that FLT3 is capable of playing a role within this compartment by examining the effects of constitutively activated FLT3-ITD. This indicates an important link between stem cell quiescence/homeostasis and myeloproliferative disease while also giving novel insight into the emergence of FLT3-ITD mutations in the evolution of leukemic transformation.
Copyright © 2012 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bone Marrow / drug effects
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Bone Marrow / metabolism
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Bone Marrow / pathology
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Bone Marrow Neoplasms / genetics
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Bone Marrow Neoplasms / pathology*
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Cell Compartmentation / drug effects
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Cell Cycle / drug effects
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Cell Proliferation / drug effects
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Enzyme Activation / drug effects
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Female
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Gene Duplication* / drug effects
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Knock-In Techniques*
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Hematopoietic Stem Cell Transplantation
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Hematopoietic Stem Cells / drug effects
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Hematopoietic Stem Cells / metabolism
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Hematopoietic Stem Cells / pathology*
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Homeostasis* / drug effects
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Homeostasis* / genetics
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Male
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Mice
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Neoplastic Stem Cells / drug effects
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology
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Niacinamide / analogs & derivatives
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Niacinamide / pharmacology
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Phenotype
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Phenylurea Compounds / pharmacology
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Promoter Regions, Genetic / genetics
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Side-Population Cells / drug effects
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Side-Population Cells / metabolism
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Side-Population Cells / pathology
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Signal Transduction / drug effects
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Small Molecule Libraries / pharmacology
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Sorafenib
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Tandem Repeat Sequences / genetics*
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fms-Like Tyrosine Kinase 3 / genetics*
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fms-Like Tyrosine Kinase 3 / metabolism
Substances
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Phenylurea Compounds
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RNA, Messenger
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Small Molecule Libraries
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Niacinamide
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Sorafenib
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Flt3 protein, mouse
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fms-Like Tyrosine Kinase 3