Different roles of E proteins in t(8;21) leukemia: E2-2 compromises the function of AETFC and negatively regulates leukemogenesis

Significance AML1-ETO–containing transcription factor complex (AETFC) is a recently identified unique multiprotein complex through which AML1-ETO controls leukemogenesis. In this study, we found a functionally important AETFC heterogeneity defined by the three E proteins: while HEB and E2A facilitate leukemogenesis, E2-2 functions as a negative regulator. The underlying mechanism involves E2-2–mediated redistribution of AETFC to specific target genes, enabling a dendritic differentiation of the leukemic cells. Consistent with the fact that E2-2 is absent in AML1-ETO–expressing leukemic cell lines, E2-2 silencing/repression may occur as a cooperative event in some t(8;21) AML patients. An E2-2 target gene is identified as a predictor of relapse in the patients. This study thus provides insights into the mechanism of AML1-ETO–associated leukemogenesis and carries prognostic/therapeutic implications.