AML1-ETO expression is directly involved in the development of acute myeloid leukemia in the presence of additional mutations

Abstract

The t(8;21) is one of the most frequent chromosomal abnormalities associated with acute myeloid leukemia (AML). The translocation, which involves the AML1 gene on chromosome 21 and the ETO gene on chromosome 8, generates an AML1-ETO fusion transcription factor. To examine the effect of the AML1-ETO fusion protein on leukemogenesis, we made transgenic mice in which expression of AML1-ETO is under the control of the human MRP8 promoter (hMRP8-AML1-ETO). AML1-ETO is specifically expressed in myeloid cells, including common myeloid progenitors of hMRP8-AML1-ETO transgenic mice. The transgenic mice were healthy during their life spans, suggesting that AML1-ETO alone is not sufficient for leukemogenesis. However, after treatment of newborn hMRP8-AML1-ETO transgenic mice and their wild-type littermates with a strong DNA-alkylating mutagen, N-ethyl-N-nitrosourea, 55% of transgenic mice developed AML and the other 45% of transgenic mice and all of the wild-type littermates developed acute T lymphoblastic leukemia. Our results provide direct evidence that AML1-ETO is critical for causing myeloid leukemia, but one or more additional mutations are required for leukemogenesis. The hMRP8-AML1-ETO-transgenic mice provide an excellent model that can be used to isolate additional genetic events and to further understand the molecular pathogenesis of AML1-ETO-related leukemia.T he acute myeloid leukemia (AML)-1 gene (AML1, also known as CBFA2, PEBP2␣B, and RUNX1) was initially identified as a target of chromosomal translocation in t(8;21), which is associated with Ϸ15% of AML (1-3). This translocation involves the AML1 gene on chromosome 21 and the ETO (MTG8) gene on chromosome 8, and generates an AML1-ETO fusion transcription factor (4). This fusion protein consists of the N terminus of AML1 fused to a nearly full-length ETO protein (4). Native AML1 is able to form a heterodimer with CBF␤ (PEBP2␤) and regulate the transcription of target genes by binding to the DNA sequence TGT͞cGGT through its runt homology domain (5-7). Subsequently, AML1 was also found to be disrupted by several other translocations, including AML1-Evi1 from t(3;21) in blast crises of chronic myeloid leukemia and in therapy-related AML (8, 9); TEL-AML1 from t(12;21), which is involved in Ϸ25% of childhood pre-B cell acute lymphoblastic leukemia (10); AML1-MTG16 from t(16;21) in rare cases of AML (11); and in radiation-associated AML (12). Furthermore, the function of AML1 is disrupted indirectly by the inv(16) that is found in 12-15% of AML cases (13). The inv(16) fuses MYH11, a smooth muscle myosin heavy chain gene, to the gene that encodes core-binding factor ␤ (CBF␤), an AML1 heterodimeric partner. Thus, translocations targeting the AML1͞ CBF␤ transcription factor complex are among the most frequent mutations in human acute leukemia.Although in vitro studies have revealed the oncogenic potential of the AML1-ETO fusion gene, they do not fully represent the molecular pathogenesis of AML. Therefore, we and other groups have developed mouse models with the AML...

Hereditary thrombocytopenia and acute myeloid leukemia: a common link due to a germline mutation in the AML1 gene

“…It may be a common underlying mechanism for the pathogenesis in AML1-associated leukemia. However, recently generated transgenic or knock-in mice showed that AML1 mutations are critical for the development of AML, but that one or more additional mutations are necessary for leukemogenesis [10][11][12]. This accepted hypothesis is supported by the cytogenetic findings in the case of our patient exhibiting a complex karyotype.…”

Histone deacetylase inhibitors induce the degradation of the t(8;21) fusion oncoprotein

“…, 2004). RUNX1-ETO expression in conjunction with treatment with the mutagen N-ethyl-N-nitrosourea (ENU) resulted in myeloid leukemia or granulocytic sarcoma (Yuan et al, 2001;Higuchi et al, 2002). Therefore, RUNX1-ETO is able to predispose myeloid precursors to transformation.…”

Correlation between karyotype and quantitative immunophenotype in acute myelogenous leukemia with t(8;21)

“…3 The creation of AML1-ETO is necessary, but not sufficient, for leukemogenesis in AML with t(8;21). 4 The recently developed WHO classification of hematologic malignancies recognizes AML with t(8;21) as a distinct clinicopathologic entity. 5 This form of AML is found more frequently in children and young adults 6 and patients are predisposed to extramedullary localization.…”