Diagram of the multistep leukemogenesis process associated with t(8;21). This model shows that after the initial event of t(8;21) within the hematopoietic stem cells (HSC) or multipotential progenitor (MPP), the cells will initially expand by the stem cell renewal program induced by the AML1-ETO fusion proteins associated with a block in myeloid differentiation. The loss of DNA repair mechanisms elicited by AML1-ETO creates an ideal environment for the acquisition of additional transforming mutagenic events such as FLT3 and Ras or deregulation of the NCoR/SMRT pathway. However, the appearance of alternative splice variants such as AML1-ETO9a may contribute to the speed of transformation or may even cooperate with AML1-ETO, being itself a secondary event by deregulated alternative splicing. The expression of AML1-ETO isoforms may also further aid in the gain and/or loss of genomic material often observed in t(8;21) leukemia through the deregulation of the mitotic checkpoint.