fim-1 and fim-2: two new integration regions of Friend murine leukemia virus in myeloblastic leukemias

Abstract

The Friend helper murine leukemia virus (F-MuLV) induces in mice a high percentage of myeloblastic leukemias. Myeloblastic transformation is also observed after in vitro infection of long-term bone marrow cultures. To investigate the molecular events leading to the generation of myeloblastic leukemias, we first screened a panel of leukemic cells for rearrangement or amplification of known oncogenes or previously described specific integration sites. No modification of these genes was observed. Therefore, we searched for common integration sites by constructing a genomic library from a myeloblastic cell line harboring only five integrated proviruses. This library was screened with a virus-specific probe, and virus-host cellular junction fragments were subcloned. Two flanking cellular sequences corresponding to two different integrated proviruses were used to analyze additional myeloblastic leukemias. The first probe detected rearrangements in 2 of 42 myeloblastic leukemias, and the second probe detected rearrangements in 6 of 42. We demonstrated that, in each case, the rearrangement was the result of F-MuLV integration, with all proviruses in the same orientation and clustering in a region less than 3 kilobases long. The two regions, named fim-1 and fim-2, were different from 15 oncogenes tested. Rearrangements of these two regions were found in F-MuLV-induced myeloblastic leukemias but not in 20 lymphoid or erythroid leukemias induced by the same virus.