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AML1 and the AML1-ETO fusion protein in the pathogenesis of t(8;21) AML

Oncogene volume 20, pages 5660–5679 (2001)Cite this article

The past decade has yielded immense progress in the understanding of the pathogenesis of acute leukemia. The cloning of consistent chromosomal breakpoints associated with particular subtypes of leukemia has led to the identification of fusion proteins largely responsible for disease pathogenesis. The AML1 gene is frequently affected in acute myeloid leukemia (Look, 1997; Mitelman and Heim, 1992). The t(8;21) (q21;q22) translocation associated with the M2 form of AML, is among the commonest rearrangements found in AML. The importance of the AML1 (now known as Runx1) gene and its heterodimeric partner CBFβ in normal and malignant hematopoiesis was apparent by the identification of these factors as critical regulators of normal myeloid-specific transcription, the involvement of both genes in leukemic translocations and the failure of hematopoiesis upon deletion of these genes. The role of AML1/RUNX in normal hematopoiesis has been extensively studied. Much less is known about the Eight-Twenty One oncoprotein (ETO)/MTG8 protein, which was unknown prior to its identification as a fusion partner. In this overview the roles of the AML1 and ETO proteins will be reviewed individually. The way in which the function of AML1 might be subverted by the leukemogenic fusion protein and its therapeutic implications will be explored.

The AML1 transcription factor was originally characterized by the study of the murine polyoma virus enhancer and the identification of similar cis-acting sequences in the promoters of hematopoietic genes. The DNA binding factor that recognizes these sequences was called polyoma enhancer binding protein 2 (PEBP2) and was found to be composed of two subunits (Kamachi et al., 1990). The activity was also known as core binding factor (CBF) for the ability of this complex to bind to a core enhancer sequence of the Moloney leukemia virus LTR (Golemis et al., 1990). The first molecular cloning of the CBF components came with the characterization of the fusion gene of the M2 form of AML associated with t(8;21). This gene was named AML1 (Miyoshi et al., 1991) and was found fused to a novel gene called Eight-Twenty One oncoprotein (ETO) (Erickson et al., 1992) or Myeloid translocation gene on chromosome 8 (MTG8) (Miyoshi et al., 1993). With subsequent cloning of the murine PEBP2/CBF genes it was realized that AML1 was the human homologue of the DNA binding subunit of PEBP2 (Ogawa et al., 1993b). The resulting predicted AML1 proteins were found to be highly homologous to a Drosophila transcriptional regulator known as runt (Kania et al., 1990). Also within a short period of time in 1993 the non-DNA binding subunit of PEBP2 was cloned and called PEBP2β or CBFβ (core binding factor β). This subunit too was found involved in leukemia, specifically in M4 AML associated with inversion 16 (Liu et al., 1993). In this case, the β subunit of the core complex was found fused to smooth muscle myosin heavy chain. These findings quickly focused a great deal of attention on the AML1/PEBP2/CBF transcription complex and have yielded competing and potentially confusing nomenclature. Table 1 indicates the names of the subunits involved in the normal and oncogenic forms of the AML1 complex and the HUGO recognized names.

Table 1 The RUNX and ETO family genes
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Acknowledgements

Supported by NIH Grant CA59936 and ACS DHP 160. I would like to thank Scott Hiebert for his advice and for sharing unpublished results and Melanie McConnell and Dong-Er Zhang for critical reading of the manuscript.

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  1. Derald H. Ruttenberg Cancer Center and Department of Medicine, Mount Sinai School of Medicine, Box 1130, One Gustave L. Levy Place, New York, NY 10029, USA

    Jonathan D Licht

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Licht, J. AML1 and the AML1-ETO fusion protein in the pathogenesis of t(8;21) AML. Oncogene 20, 5660–5679 (2001). https://doi.org/10.1038/sj.onc.1204593

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