PMID- 9558367 OWN - NLM STAT- MEDLINE DCOM- 19980521 LR - 20220224 IS - 0006-4971 (Print) IS - 0006-4971 (Linking) VI - 91 IP - 9 DP - 1998 May 1 TI - Expression of a knocked-in AML1-ETO leukemia gene inhibits the establishment of normal definitive hematopoiesis and directly generates dysplastic hematopoietic progenitors. PG - 3134-43 AB - 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. FAU - Okuda, T AU - Okuda T AD - Departments of Pathology and Laboratory Medicine, Tumor Cell Biology, and Genetics, St Jude Children's Research Hospital, Memphis, TN, USA. FAU - Cai, Z AU - Cai Z FAU - Yang, S AU - Yang S FAU - Lenny, N AU - Lenny N FAU - Lyu, C J AU - Lyu CJ FAU - van Deursen, J M AU - van Deursen JM FAU - Harada, H AU - Harada H FAU - Downing, J R AU - Downing JR LA - eng GR - CA-21765/CA/NCI NIH HHS/United States GR - P01 CA71907-01/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. PL - United States TA - Blood JT - Blood JID - 7603509 RN - 0 (Core Binding Factor Alpha 2 Subunit) RN - 0 (DNA-Binding Proteins) RN - 0 (Neoplasm Proteins) RN - 0 (Proto-Oncogene Proteins) RN - 0 (RUNX1 Translocation Partner 1 Protein) RN - 0 (RUNX1T1 protein, human) RN - 0 (Recombinant Fusion Proteins) RN - 0 (Runx1 protein, mouse) RN - 0 (Transcription Factors) SB - IM MH - Animals MH - Bone Marrow Cells/pathology MH - Core Binding Factor Alpha 2 Subunit MH - DNA-Binding Proteins/*genetics MH - Gene Expression Regulation, Developmental MH - Genes, Lethal MH - *Hematopoiesis MH - Hematopoietic Stem Cells/cytology MH - Heterozygote MH - Leukemia, Myeloid, Acute/*genetics/pathology MH - Liver/embryology MH - Mice MH - Mice, Transgenic MH - Neoplasm Proteins/genetics MH - *Proto-Oncogene Proteins MH - RUNX1 Translocation Partner 1 Protein MH - Recombinant Fusion Proteins MH - Transcription Factors/*genetics MH - Yolk Sac/cytology EDAT- 1998/05/23 00:00 MHDA- 1998/05/23 00:01 CRDT- 1998/05/23 00:00 PHST- 1998/05/23 00:00 [pubmed] PHST- 1998/05/23 00:01 [medline] PHST- 1998/05/23 00:00 [entrez] AID - S0006-4971(20)55218-X [pii] PST - ppublish SO - Blood. 1998 May 1;91(9):3134-43.