GATA2 haploinsufficiency accelerates EVI-1-driven leukemogenesis in an inv(3)(q21q26) mouse model

Abstract

Chromosomal rearrangements between 3q21 and 3q26 give rise to acute myeloid leukemia (AML) with poor prognosis. The rearrangements induce inappropriate EVI1 expression by recruiting a GATA2-distal hematopoietic enhancer (G2DHE) to the proximity of EVI1, which is the major cause of leukemogenesis. The acquisition of G2DHE by EVI1 reciprocally deprives this enhancer of one of the two GATA2 alleles, resulting in reduced GATA2 expression. As GATA2 deficiency is strongly associated with AML, we examined whether reduced GATA2 expression also contributes to leukemogenesis by using the 3q21q26 transgenic mouse model that recapitulates the G2DHE-driven EVI1 misexpression. To analyze the contribution of reduced GATA2 expression, we crossed 3q21q26 mice with Gata2 heterozygous knockout mice. Of note, 3q21q26::Gata2+/− mice developed leukemia faster than 3q21q26 mice, indicating that Gata2 heterozygous deletion promotes the EVI1-provoked leukemic transformation. In the leukemic 3q21q26 mice, B220+ and Gr1+ cells occupied their bone marrows. Transplantation analysis showed that the B220+ population contained leukemia-initiating cells and differentiated into Gr1+ leukemia cells. In the 3q21q26::Gata2+/− mice, the differentiation of the B220+ cells was suppressed and the cells showed enhanced proliferation. In conclusion, GATA2 haploinsufficiency accelerates leukemogenesis associated with 3q rearrangement.