NEOPLASTIC TRANSFORMATION OF NORMAL HEMATOPOIETIC-CELLS BY CONSTITUTIVELY ACTIVATING MUTATIONS OF C-KIT RECEPTOR TYROSINE KINASE

The c-kit proto-oncogene encodes a receptor tyrosine kinase that is cr ucial to hematopoiesis, melanogenesis, and garnetogeneis. Although the enzymatic activity of the c-kit product (KIT) is regulated by its lig and, both the Val559 --> Gly (G559) mutation in the juxtamembrane doma in and the Asp814 --> Val (V814) mutation in the phosphotransferase do main lead to constitutive activation of KIT. By retroviral infection o f hematopoietic progenitor cells with KITG559 Or KITV814, KITG559 indu ced development of granulocyte/macrophage and mast-cell colonies in vi tro without the addition of exogenous growth factors. KITV814 induced factor-independent growth of various types of hematopoietic progenitor cells, resulting in the development of mixed erythroid/myeloid coloni es in addition to granulocyte/macrophage and mast-cell colonies. Furth ermore, transplantation of KITG559 and KITV814-infected bone marrow ce lls led to development of acute leukemia in one of 10 and six of 10 tr ansplanted mice, respectively. No mice developed hematologic malignanc ies after transplantation of wild-type KIT-infected cells. Furthermore , transgenic mice expressing KITV814 developed acute leukemia or malig nant lymphoma. These results demonstrate a direct role of the mutant K ITs, particularly KITV814, in tumorigenesis of hematopoietic cells and suggest that similar mutations may contribute to the development of h uman hematologic malignancies. (C) 1996 by The American Society of Hem atology.