ACTIVATION OF QUIESCENT ABL-TRANSDUCED HEMATOPOIETIC 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 bee n 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 quies cent without causing a disease for an extended period of time. Recipie nt mice were able to survive more than one treatment of 5-fluorouracil (5-FU) at a dose that normally eliminates cycling hemopoietic progeni tor cells; subsequently, transduced HSCs could become activated and un dergo clonal expansion, resulting in abl-induced leukemic development. The disease developed in these mice was transplantable. Upon engraftm ent into secondary mice, previously unidentified abl-transduced HSC cl ones appeared. These data suggest the presence of an abl-suppressive m echanism in HSCs and have important implications to the pathogenesis o f stem cell diseases and leukemic clonal evolution.