Chromosomal rearrangements between 3q21 and 3q26 induce leukemogenesis by misdirecting both EVI1 and GATA2 genes.

Chromosomal rearrangements between 3q21 and 3q26 induce the abnormal expression of the EVI1 gene on 3q26, which results in leukemia and a poor prognosis. In the rearranged allele, we found that the GATA2 gene enhancer on 3q21 localizes in close proximity to the EVI1 gene. To examine the contribution of the GATA2 gene enhancer upon the abnormal expression of EVI1 and leukemogenesis, we established a leukemia mouse model (3q21q26 mouse) harboring a transgene recapitulating a 196-kb inverted allele between 3q21 and 3q26 by linking two bacterial artificial chromosome clones. The 3q21q26 mice demonstrated high EVI1 transgene expression specifically in hematopoietic progenitors and developed leukemia after 6 months of age. Of note, by deleting the GATA2 enhancer, EVI1 transgene expression and leukemogenesis were significantly suppressed, indicating that the GATA2 enhancer drives the abnormal expression of EVI1 in the rearranged allele and induces leukemogenesis. While the EVI1 gene gains the GATA2 enhancer, GATA2 gene loses its enhancer. Therefore, GATA2 expression levels are reduced in leukemic cells with such chromosomal rearrangements. To examine the contribution of GATA2 heterozygous deletion upon leukemogenesis, we crossed the 3q21q26 mice with Gata2 heterozygous knockout mice to generate compound mutant mice recapitulating both abnormal EVI1 expression and Gata2 heterozygous deletion. The compound mutant mice developed leukemia earlier than the 3q21q26 mice did. These results indicate that GATA2 heterozygous deletion accelerates leukemogenesis driven by the abnormal expression of EVI1.