Analysis of the mechanism of leukemogenesis caused by abnormal expressions of EVI1 and GATA2

Abstract

Acute myeloid leukemia (AML) with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2), which accounts for 1–2% of AML cases, has a poor prognosis. A high expression level of EVI1 is known to be one of its feature, but the mechanism underlying this abnormal expression is as yet not known. Our group has established a transgenic mouse model (3q21q26-EVI1 mice) that recapitulates the inverted allele between 3q21 and 3q26 by linking two bacterial artificial chromosome (BAC) clones. By utilizing the 3q21q26-EVI1 mice, we found that the far upstream enhancer of GATA2 (G2DHE) activates EVI1 expression, leading to the development of leukemia. Furthermore, by comparing leukemogenesis in 3q21q26-EVI1 mice with that in mice with combined 3q21q26-EVI1 and GATA2 heterozygous deletion, we examined how a reduced GATA2 expression modulates EVI1-driven leukemogenesis. As a result, we demonstrated that in 3q21q26 leukemia in addition to the induction of EVI1 expression by the GATA2 enhancer, the mechanism of GATA2 haploinsufficiency is also important in leukemogenesis. The 3q21q26-EVI1 mice are the only mouse model that successfully recapitulates the increase in the number of megakaryocytes and platelets, which is a characteristic phenotype of human 3q21q26 leukemia. Mouse models established using BAC linking technology may also be a useful tool for elucidating the pathogenesis of other types of leukemia with chromosomal aberrations.