Retroviruses lacking oncogenes induce tumors or leukemias after a long latency which generally exceeds several months. Cellular transformation most probably results from the activation of cellular oncogenes or putative proto-oncogenes due to proviral integration. Several genetic changes are likely to be necessary for the appearance of fully malignant cells. However, the sequence of genetic changes initiating and leading to malignant transformation is difficult to study since, in most experimental conditions, the only accessible cells are fully transformed cells. We have previously described an in vitro model of murine myeloblastic leukemogenesis during which several successive steps leading to fully malignant and transplantable cells have been identified. This in vitro transformation process develops over approximately a 1-year period. In this paper, we demonstrate that frequent cellular DNA rearrangements due to proviral integrations in specific regions occur early in the myeloblastic transformation process and remain stable throughout the in vitro leukemogenesis, and in tumors derived from in vitro fully transformed myeloblasts.