| First Author | Okuda T | Year | 1998 |
| Journal | Blood | Volume | 91 |
| Issue | 9 | Pages | 3134-43 |
| PubMed ID | 9558367 | Mgi Jnum | J:79160 |
| Mgi Id | MGI:2387294 | Doi | 10.1182/blood.v91.9.3134.3134_3134_3143 |
| Citation | Okuda T, et al. (1998) Expression of a knocked-in AML1-ETO leukemia gene inhibits the establishment of normal definitive hematopoiesis and directly generates dysplastic hematopoietic progenitors. Blood 91(9):3134-43 |
| abstractText | The t(8;21)-encoded AML1-ETO chimeric product is believed to be causally involved in up to 15% of acute myelogenous leukemias through an as yet unknown mechanism. To directly investigate the role of AML1-ETO in leukemogenesis, we used gene targeting to create an AML1-ETO 'knock-in' allele that mimics the t(8;21). Unexpectedly, embryos heterozygous for AML1-ETO (AML1-ETO/+) died around E13.5 from a complete absence of normal fetal liver-derived definitive hematopoiesis and lethal hemorrhages. This phenotype was similar to that seen following homozygous disruption of either AML1 or CBFbeta. However, in contrast to AML1- or CBFbeta-deficient embryos, fetal livers from AML1-ETO/+ embryos contained dysplastic multilineage hematopoietic progenitors that had an abnormally high self-renewal capacity in vitro. To further document the role of AML1-ETO in these growth abnormalities, we used retroviral transduction to express AML1-ETO in murine adult bone marrow-derived hematopoietic progenitors. AML1-ETO-expressing cells were again found to have an increased self-renewal capacity and could be readily established into immortalized cell lines in vitro. Taken together, these studies suggest that AML1-ETO not only neutralizes the normal biologic activity of AML1 but also directly induces aberrant hematopoietic cell proliferation. |
