TY - JOUR
T1 - Expression of a knocked-in AML1-ETO leukemia gene inhibits the establishment of normal definitive hematopoiesis and directly generates dysplastic hematopoietic progenitors
AU - Okuda, Tsukasa
AU - Cai, Zhongling
AU - Yang, Shouli
AU - Lenny, Noel
AU - Lyu, Chuhl Joo
AU - Van Deursen, Jan M.A.
AU - Harada, Hironori
AU - Downing, James R.
PY - 1998/5/1
Y1 - 1998/5/1
N2 - 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 CBFβ. However, in contrast to AML1- or CBFβ-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.
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 CBFβ. However, in contrast to AML1- or CBFβ-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.
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U2 - 10.1182/blood.v91.9.3134.3134_3134_3143
DO - 10.1182/blood.v91.9.3134.3134_3134_3143
M3 - Article
C2 - 9558367
AN - SCOPUS:0032079424
SN - 0006-4971
VL - 91
SP - 3134
EP - 3143
JO - Blood
JF - Blood
IS - 9
ER -