GATA2 haploinsufficiency accelerates EVI1-driven leukemogenesis.

Chromosomal rearrangements between 3q21 and 3q26 induce inappropriate expression by recruiting a -distal hematopoietic enhancer (G2DHE) to the proximity of the gene, leading to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The acquisition of G2DHE by the gene reciprocally deprives this enhancer of 1 of the 2 alleles, resulting in a loss-of-function genetic reduction in abundance. Because haploinsufficiency is strongly associated with MDS and AML, we asked whether misexpression and haploinsufficiency both contributed to the observed leukemogenesis by using a 3q21q26 mouse model that recapitulates the G2DHE-driven misexpression, but in this case, it was coupled to a heterozygous germ line deletion. Of note, the heterozygous deletion promoted the -provoked leukemic transformation, resulting in early onset of leukemia. The 3q21q26 mice suffered from leukemia in which B220 cells and/or Gr1 leukemic cells occupied their bone marrows. We found that the B220Gr1c-Kit population contained leukemia-initiating cells and supplied Gr1 leukemia cells in the 3q21q26 leukemia. When expression levels in the B220Gr1c-Kit cells were decreased as a result of heterozygous deletion or spontaneous phenomenon, myeloid differentiation of the B220Gr1c-Kit cells was suppressed, and the cells acquired induced proliferation as well as B-lymphoid-primed characteristics. Competitive transplantation analysis revealed that heterozygous deletion confers selective advantage to EVI1-expressing leukemia cell expansion in recipient mice. These results demonstrate that both the inappropriate stimulation of and the loss of 1 allele equivalent of expression contribute to the acceleration of leukemogenesis.