Activation of quiescent ABL-transduced hemopoietic stem cells.
Chronic myelogenous leukemia (CML) is a hemopoietic stem cell disorder in which an activated ABL oncogene is expressed and has been shown to play an important role in disease pathogenesis. A mouse model has been established in which hemopoietic stem cells (HSCs) transduced with a retrovirus vector carrying an activated ABL oncogene can be analysed. Using this model, we now report that abl-transduced HSCs can be quiescent without causing a disease for an extended period of time. Recipient mice were able to survive more than one treatment of 5-fluorouracil (5-FU) at a dose that normally eliminates cycling hemopoietic progenitor cells; subsequently, transduced HSCs could become activated and undergo clonal expansion, resulting in abl-induced leukemic development. The disease developed in these mice was transplantable. Upon engraftment into secondary mice, previously unidentified abl-transduced HSC clones appeared. These data suggest the presence of an abl-suppressive mechanism in HSCs and have important implications to the pathogenesis of stem cell diseases and leukemic clonal evolution.
Chung
S W
SW
Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Chen
H
H
Wong
P M
PM
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D005472:Fluorouracil / Q000494:pharmacology*; D016313:Genes, abl / Q000235:genetics*; D005822:Genetic Vectors; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D014162:Transfection; D016662:Virus Integration
D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil