AML1-ETO9a, an Alternatively Spliced Form of AML1-ETO, Collaborates with AML1-ETO To Promote Leukemogenesis.

t(8;21) is a common chromosome translocation in acute myeloid leukemia (AML). AML1-ETO is the fusion protein produced by t(8;21). Results from our work and others indicate that full length AML1-ETO is not leukemogenic and needs additional mutations to promote leukemia. Most recently, we have identified an alternatively spliced form of AML1-ETO, AML1-ETO9a, that lacks the C-terminal NHR₃ and NHR₄ domains of AML1-ETO. Here, we report that unlike the negative effect of full length AML1-ETO in cell cycle progression, AML1-ETO9a enhances cell proliferation by shortening G1 phase of cell cycle in the IL-3 dependent multipotent hematopoietic progenitor cell line FDCPmix. Using retroviral mediated gene expression in murine hematopoietic cells and bone marrow transplantation in mice, we have demonstrated that AML1-ETO9a is highly leukemogenic. Most importantly, we show that AML1-ETO9a expression in transgenic MRP-8 AML1-ETO hematopoietic cells results in earlier onset of AML than AML1-ETO9a expression alone controls. Furthermore, the presence of full length AML1-ETO also alters the phenotype of leukemia progenitor cells from CD34- to CD34+. These results suggest that the alternatively spliced form AML1-ETO9a cooperates with full length AML1-ETO in leukemogenesis when coexpressed in t(8;21) patients.