FLT3-ITD Knockin Impairs Hematopoietic Stem Cell Quiescence/Homeostasis, Leading to Myeloproliferative Neoplasm

• Published in: Cell stem cell 2012-09, Vol.11 (3), p.346-358
• Main Authors: Chu, S. Haihua, Heiser, Diane, Li, Li, Kaplan, Ian, Collector, Michael, Huso, David, Sharkis, Saul J., Civin, Curt, Small, Don
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Bone Marrow - drug effects; Bone Marrow - metabolism; Bone Marrow - pathology; Bone Marrow Neoplasms - genetics; Bone Marrow Neoplasms - pathology; Cell Compartmentation - drug effects; Cell Cycle - drug effects; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Cell Proliferation - drug effects; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Enzyme Activation - drug effects; Female; fms-Like Tyrosine Kinase 3 - genetics; fms-Like Tyrosine Kinase 3 - metabolism; Fundamental and applied biological sciences. Psychology; Gene Duplication - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Gene Knock-In Techniques; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - pathology; Homeostasis - drug effects; Homeostasis - genetics; Male; Mice; Molecular and cellular biology; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Niacinamide - analogs & derivatives; Niacinamide - pharmacology; Phenotype; Phenylurea Compounds - pharmacology; Promoter Regions, Genetic - genetics; RNA, Messenger - genetics; RNA, Messenger - metabolism; Side-Population Cells - drug effects; Side-Population Cells - metabolism; Side-Population Cells - pathology; Signal Transduction - drug effects; Small Molecule Libraries - pharmacology; Sorafenib; Tandem Repeat Sequences - genetics
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2012.05.027

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. ► FLT3-ITD perturbs normal mouse hematopoietic stem cell homeostasis ► FLT3 is expressed and capable of exerting functional effects in murine LT-HSCs ► FLT3-ITD leads to depletion of murine LT-HSCs through loss of quiescence ► MPN and HSC defects are simultaneously reversed by Sorafenib treatment The FLT3 receptor, frequently mutated in acute myeloid leukemia, is not believed to be expressed in HSCs. A constitutively active FLT3-ITD mutation in mice drives depletion of LT-HSCs and is coupled with rapid myeloproliferation, suggesting an unrecognized link between HSCs homeostasis and disease.