EVI1is critical for the pathogenesis of a subset of MLL-AF9–rearranged AMLs

The proto-oncogene EVI1(ecotropic viral integration site-1), located on chromosome band 3q26, is aberrantly expressed in human acute myeloid leukemia (AML) with 3q26 rearrangements. In the current study, we showed, in a large AML cohort carrying 11q23 translocations, that ∼ 43% of all mixed lineage leukemia (MLL)–rearranged leukemias are EVI1pos. High EVI1expression occurs in AMLs expressing the MLL-AF6, -AF9, -AF10, -ENL, or -ELLfusion genes. In addition, we present evidence that EVI1posMLL-rearranged AMLs differ molecularly, morphologically, and immunophenotypically from EVI1negMLL-rearranged leukemias. In mouse bone marrow cells transduced with MLL-AF9, we show that MLL-AF9 fusion protein maintains Evi1expression on transformation of Evi1posHSCs. MLL-AF9 does not activate Evi1expression in MLL-AF9–transformed granulocyte macrophage progenitors (GMPs) that were initially Evi1neg. Moreover, shRNA-mediated knockdown of Evi1in an Evi1posMLL-AF9mouse model inhibits leukemia growth both in vitro and in vivo, suggesting that Evi1provides a growth-promoting signal. Using the Evi1posMLL-AF9mouse leukemia model, we demonstrate increased sensitivity to chemotherapeutic agents on reduction of Evi1expression. We conclude that EVI1is a critical player in tumor growth in a subset of MLL-rearranged AMLs.