BCR-ABL EFFICIENTLY INDUCES A MYELOPROLIFERATIVE DISEASE AND PRODUCTION OF EXCESS INTERLEUKIN-3 AND GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR IN MICE - A NOVEL MODEL FOR CHRONIC MYELOGENOUS LEUKEMIA

The bcr-abl oncogene plays a critical role in causing chronic myelogen ous leukemia (CML). Effective laboratory animal models of CML are need ed to study the molecular mechanisms by which the bcr-abl oncogene act s in the disease progression of CML. We used a murine stem cell retrov iral vector (MSCV) to transduce the bcr-abl/p210 oncogene into mouse b one marrow cells and found that expression of Bcr-Abl/p210 induced a m yeloproliferative disorder that resembled the chronic phase of human C ML in 100% of bone marrow transplanted mice in about 3 weeks. This CML -like disease was readily transplanted to secondary recipient mice. Mu ltiple clones of infected cells were expanded in the primary recipient s, but the leukemia was primarily monoclonal in the secondary recipien t mice. Mutation analysis demonstrated that the protein tyrosine kinas e activity of Bcr-Abl/p210 was essential for its leukemogenic potentia l in vivo. Interestingly, we found that the leukemic cells expressed e xcess interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulati ng factor (GM-CSF) in the diseased mice. These studies demonstrate tha t expression of Bcr-Abl can induce a CML-like leukemia in mice much mo re efficiently and reproducibly than in previously reported mouse CML models, probably due to efficient expression in the correct target cel l(s). Our first use of this model for analysis of the molecular mechan isms involved in CML raises the possibility that excess expression of hematopoietic growth factors such as IL-3 and GM-CSF may contribute to the clinical phenotype of CML. (C) 1998 by The American Society of He matology.