title: FLT3-ITD knockin impairs hematopoietic stem cell quiescence/homeostasis, leading to myeloproliferative neoplasm.
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.
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: S Haihua
authors.initials: SH
authors.lastname: Chu
authors.forename: Diane
authors.initials: D
authors.lastname: Heiser
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Ian
authors.initials: I
authors.lastname: Kaplan
authors.forename: Michael
authors.initials: M
authors.lastname: Collector
authors.forename: David
authors.initials: D
authors.lastname: Huso
authors.forename: Saul J
authors.initials: SJ
authors.lastname: Sharkis
authors.forename: Curt
authors.initials: C
authors.lastname: Civin
authors.forename: Don
authors.initials: D
authors.lastname: Small
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019046:Bone Marrow Neoplasms / Q000235:genetics / Q000473:pathology*; D002451:Cell Compartmentation / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D020440:Gene Duplication / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055879:Gene Knock-In Techniques; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010641:Phenotype; D010671:Phenylurea Compounds / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D058985:Side-Population Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology; D000077157:Sorafenib; D020080:Tandem Repeat Sequences / Q000235:genetics*; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics* / Q000378:metabolism
chemical_list: D010671:Phenylurea Compounds; D012333:RNA, Messenger; D054852:Small Molecule Libraries; D009536:Niacinamide; D000077157:Sorafenib; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3