The overall objective of the laboratory is to develop mouse model systems for studying acute myeloid leukemia. With the use of different retroviruses several leukemias within the monocyte-macrophage lineage have been induced in mice undergoing a chronic inflammatory response. Since the effect of oncogene activation in these leukemias is a major interest of the laboratory, two types of studies are being pursued in this area at the present time. One study is aimed at examining the various mechanisms by which c-myb can be activated by viral insertional mutagenesis Insertional mutagenesis by Moloney murine leukemia virus (MuLV) in our promonocytic leukemias results in very characteristic RNA and protein products, however insertional mutagenesis of c-myb by FB29 is only partially characterized. So far we have demonstrated that the c- myb protein products from these leukemias are unique. They probably result from unique hybrid RNAs in which gag and myb sequences are juxta- posed and these are presently being characterized in more detail. There is also an ongoing interest in insertional mutagenesis at other sites in the genome. Clonal integration sites of Moloney MuLV, Ampho 4070, and FB29 into the mouse genome of leukemias have been characterized and selected integration sites have been cloned into lambda phage. Cloned sequences will be used to search for common integration sites amongst leukemias. Another focus of the laboratory is the delineation of specific stages of disease development and trafficking of preleukemic cells. A RNA-PCR technique for detection of a molecular marker in leukemic cells has provided some information about trafficking patterns. Leukemic cells can be detected in hematopoietic organs such as bone marrow, liver, spleen and mesenteric granuloma as early as 3 wks post viral infection even though the disease is not evident until 3-4 mo. Although pristane increases the number of mice in which such cells can be detected, they can be detected even in the tissues of some mice that have not been treated with pristane. Future experiments will be aimed at extending our knowledge about trafficking and the role of hematopoietic organs in this disease.
