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Loss of c‐Kit and bone marrow failure upon conditional removal of the GATA ‐2 C‐terminal zinc finger domain in adult mice
Author(s) -
Li Haiyan S.,
Jin Jin,
Liang Xiaoxuan,
Matatall Katie A.,
Ma Ying,
Zhang Huiyuan,
Ullrich Stephen E.,
King Katherine Y.,
Sun ShaoCong,
Watowich Stephanie S.
Publication year - 2016
Publication title -
european journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.904
H-Index - 84
eISSN - 1600-0609
pISSN - 0902-4441
DOI - 10.1111/ejh.12719
Subject(s) - gata2 , bone marrow , haematopoiesis , myelopoiesis , biology , zinc finger , myeloid , cancer research , progenitor cell , mutation , immunology , microbiology and biotechnology , stem cell , transcription factor , genetics , gene
Heterozygous mutations in the transcriptional regulator GATA ‐2 associate with multilineage immunodeficiency, myelodysplastic syndrome ( MDS ), and acute myeloid leukemia ( AML ). The majority of these mutations localize in the zinc finger (ZnF) domains, which mediate GATA ‐2 DNA binding. Deregulated hematopoiesis with GATA ‐2 mutation frequently develops in adulthood, yet GATA ‐2 function in the bone marrow remains unresolved. To investigate this, we conditionally deleted the GATA ‐2 C‐terminal ZnF (C‐ZnF) coding sequences in adult mice. Upon Gata2 C‐ZnF deletion, we observed rapid peripheral cytopenia, bone marrow failure, and decreased c‐Kit expression on hematopoietic progenitors. Transplant studies indicated GATA ‐2 has a cell‐autonomous role in bone marrow hematopoiesis. Moreover, myeloid lineage populations were particularly sensitive to Gata2 hemizygosity, while molecular assays indicated GATA ‐2 regulates c‐Kit expression in multilineage progenitor cells. Enforced c‐Kit expression in Gata2 C‐ZnF‐ deficient hematopoietic progenitors enhanced myeloid colony activity, suggesting GATA ‐2 sustains myelopoiesis via a cell intrinsic role involving maintenance of c‐Kit expression. Our results provide insight into mechanisms regulating hematopoiesis in bone marrow and may contribute to a better understanding of immunodeficiency and bone marrow failure associated with GATA ‐2 mutation.