Fusion-protein truncation provides new insights into leukemogenesis

Abstract

AML1-ETO (also known as RUNX1-ETO) is the fusion-protein transcription factor product of the 8;21 translocation. The translocation is present in up to 40% of leukemias of the French-American-British M2 subtype and is one of the most common events associated with myeloid leukemia. Clarifying the role of AML1-ETO in leukemogenesis has been difficult because the expression of the oncoprotein is not sufficient to cause disease. The challenge is reflected by the number of models that have been devised to study AML1-ETO in mice. In this issue of PNAS, Zhang and colleagues (1) advance the understanding of AML1-ETO another step with the discovery that a C-terminal truncation mutation produces penetrant leukemia. The earliest attempts to model AML1-ETO-associated leukemia in mice showed that the oncoprotein has detrimental developmental effects when expressed during embryogenesis (2, 3). The phenotype of the AML1-ETO knock-in embryos strongly resembled AML1 knockout embryos. The similarity provided compelling in vivo evidence supporting the hypothesis that AML1-ETO interferes with AML1. Although the embryonic lethal phenotype of the AML1-ETO knock-in was a temporary setback in the production of a leukemia model, the observations provided important clues to the action of AML1-ETO. Subsequent mouse models were engineered to bypass the embryonic lethality of AML1-ETO. Transgenic models, inducible systems, and bone marrow transplant strategies for expressing AML1-ETO were unable to reliably produce leukemia in mice even after 24 months (4–7). However, the failure to cause leukemia was extremely enlightening. When stem cells were transduced with AML1-ETO and transplanted into lethally irradiated recipient animals, the stem cell compartment expanded dramatically (6). Similarly, direct targeting of AML1-ETO expression to stem cells by using the SCA-1 promoter enhanced myeloid progenitor expansion (7). These experiments suggested that AML1-ETO could promote the expansion of a compartment that ultimately would acquire additional “hits” leading to disease. In …