Acute myeloid leukemia (AML), a highly lethal cancer, is characterized by the uncontrolled proliferation of immature hematopoietic precursor cells in the bone marrow. Neoplasia involves a multistep process where disregulated expression of many genes cooperates to provide a growth advantage. Understanding the molecular genetic changes which occur during the development of AML will aid in the generation of more effective treatments. Although certain genes have been implicated in AML, such as the transcription factor Evi1 which was identified as a common site of retroviral integration by murine leukemia viruses, overexpression of Evi1 alone will not cause leukemia. Therefore, it is necessary to identify additional genetic alterations, which occur in cooperation with Evil. We are screening murine AMLS and tumor cell lines that have been previously characterized to overexpress Evi1 due to retroviral insertion in the Evi1 locus. Using an inverse PCR approach, we have begun cloning additional sites of integration. We have identified a second common site of retroviral integration within a novel gene occurring in 75 percent of the initial tumors examined. Some of these tumors appear to contain two independent insertions within the same locus, which is suggestive of a tumor suppressor gene. To follow up on our initial observations, we propose to: 1) further characterize this new site of integration at the levels of gene structure, putative protein function, and pattern of expression, 2) further evaluate the incidence of mutation at this locus in other retrovirally induced murine leukemias, and 3) investigate the role of this novel gene in the genesis of myeloid leukemia in rice with or without concomitant Evi 1 overexpression.
| Boyd, Kathryn E; Xiao, Ying-Yi; Fan, Kai et al. (2006) Sox4 cooperates with Evi1 in AKXD-23 myeloid tumors via transactivation of proviral LTR. Blood 107:733-41 |
