Expression of a Knocked-In AML1-ETO Leukemia Gene Inhibits the Establishment of Normal Definitive Hematopoiesis and Directly Generates Dysplastic Hematopoietic Progenitors

Abstract

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 anAML1-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 orCBFβ. 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.

Increased Cancer Incidence Following up to 15 Years after Cardiac Catheterization in Infants under One Year between 1980 and 1998—A Single Center Observational Study

“…This is in line with previous data from the Danish Cytogenic Register showing that leukemia constituted 97% of malignancies in trisomy 21 in the first 15 years of life [32]. Some of the genes on chromosome 21 have been found to be disrupted in leukemia [37]. This damage might have been boosted by ionizing radiation in our cohort.…”

RUNX Proteins as Epigenetic Modulators in Cancer

“…However, mutations of RUNX1 are detected in hematological malignancies frequently and less frequently in some solid tumors. In clinical studies, ~10% of AML patients were identified to have translocations near the RUNX1 chromosomal region [ 96 , 97 ], ~7% of esophageal cancer patients had RUNX1 deletion mutations [ 98 ], and ~4% of breast cancer patients had RUNX1 inactivating mutations ( Table 2 ) [ 17 ]. In some hematological malignancies, RUNX1 proteins have been found to fuse with other genes, such as RUNX1-ETO fusion in 10–20% of AML patients and TEL-RUNX1 fusion in 20–25% of childhood ALL patients [ 65 , 99 ].…”

The Impact of the Cellular Origin in Acute Myeloid Leukemia: Learning From Mouse Models

“…Modeling AML driven by CBF rearrangements such as the RUNX1‐RUNX1T1 (initially referred to as AML1‐ETO ) or the CBFbeta‐MYH11 fusion genes turned out to be rather difficult. Conventional knock‐in models were hampered by embryonic lethality due to the dominant‐negative impact of the fusion to wild‐type RUNX1 and CBFbeta, both essential regulators of adult hematopoiesis 48–50 . Conditional knock‐in mice demonstrated that whereas expression of the CBFbeta‐MYH11 fusion resulted in spontaneous AML after long latency, expression of RUNX1‐RUNX1T1 seemed insufficient to induce an AML phenotype 51–53 .…”