GATA2 haploinsufficiency accelerates EVI1-driven leukemogenesis

Saori Katayama, Mikiko Suzuki, Ayaka Yamaoka, Lukwete Nadine Keleku, Fumiki Katsuoka, Akihito Otsuki, Shigeo Kure, James Douglas Engel, Masayuki Yamamoto

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

Abstract

Chromosomal rearrangements between 3q21 and 3q26 induce inappropriate EVI1 expression by recruiting a GATA2-distal hematopoietic enhancer (G2DHE) to the proximity of the EVI1 gene, leading to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The acquisition of G2DHE by the EVI1 gene reciprocally deprives this enhancer of 1 of the 2 GATA2 alleles, resulting in a loss-of-function genetic reduction in GATA2 abundance. Because GATA2 haploinsufficiency is strongly associated with MDS and AML, we asked whether EVI1 misexpression and GATA2 haploinsufficiency both contributed to the observed leukemogenesis by using a 3q21q26 mouse model that recapitulates the G2DHE-driven EVI1 misexpression, but in this case, it was coupled to a Gata2 heterozygous germ line deletion. Of note, the Gata2 heterozygous deletion promoted the EVI1-provoked leukemic transformation, resulting in early onset of leukemia. The 3q21q26 mice suffered from leukemia in which B2201 cells and/or Gr11 leukemic cells occupied their bone marrows. We found that the B2201Gr1c-Kit1 population contained leukemia-initiating cells and supplied Gr11 leukemia cells in the 3q21q26 leukemia. When Gata2 expression levels in the B2201Gr1c-Kit1 cells were decreased as a result of Gata2 heterozygous deletion or spontaneous phenomenon, myeloid differentiation of the B2201Gr1c-Kit1 cells was suppressed, and the cells acquired induced proliferation as well as B-lymphoid–primed characteristics. Competitive transplantation analysis revealed that Gata2 heterozygous deletion confers selective advantage to EVI1-expressing leukemia cell expansion in recipient mice. These results demonstrate that both the inappropriate stimulation of EVI1 and the loss of 1 allele equivalent of Gata2 expression contribute to the acceleration of leukemogenesis.

Original languageEnglish
Pages (from-to)908-919
Number of pages12
JournalBlood
Volume130
Issue number7
DOIs
Publication statusPublished - 2017 Aug 17

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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