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...

Self-renewal of stem cells is critical for tissue repair and maintenance of organ integrity in most mammalian systems. The relative asymmetry between self-renewal and differentiation in balance with apoptosis determines the size and durability of a stem-cell pool. Regulation of the cell cycle is one of the fundamental mechanisms underlying determination of cell fate. Absence of p21(Cip1/Waf1), a late G1-phase cyclin-dependent kinase inhibitor (CKI), has previously been shown to enable cell-cycle entry of haematopoietic stem cells, but leads to premature exhaustion of the stem cells under conditions of stress. We show here that deletion of an early G1-phase CKI, p18(INK4C), results in strikingly improved long-term engraftment, largely by increasing self-renewing divisions of the primitive cells in murine transplant models. Therefore, different CKIs have highly distinct effects on the kinetics of stem cells, possibly because of their active position in the cell cycle, and p18(INK4C) appears to be a strong inhibitor limiting the potential of stem-cell self-renewal in vivo.