Low-level GATA2 overexpression promotes myeloid progenitor self-renewal and blocks lymphoid differentiation in mice.

ABSTRACT

The transcription factor GATA2 is highly expressed in hematopoietic stem cells and is downregulated during lineage maturation. Gain of function mutations, loss of function mutations, and overexpression of GATA2 have been reported in acute myeloid leukemia. In previous studies, we and others showed that GATA2 overexpression at high levels, similar to that seen in hematopoietic stem cells, blocked differentiation of hematopoietic stem cells and progenitors. To better understand the effects of GATA2, we designed a Tamoxifen-inducible GATA2-estrogen receptor (ERT) vector. In the absence of Tamoxifen, small amounts of GATA2-ERT were still able to enter the nucleus in mouse bone marrow (BM) cells, providing us with a tool to test the effects of low-level GATA2 overexpression. We observed that this low-level GATA2 overexpression enhanced self-renewal of myeloid progenitors in vitro and resulted in immortalization of BM cells to myeloid cell lines. Continuous GATA2-ERT expression was required for the proliferation of these immortalized lines. Myeloid expansion and a block in T and B lineage differentiation were observed in mice transplanted with GATA2-ERT-expressing BM cells. Myeloid expansion occurred after the granulocyte monocyte progenitor stage, and lymphoid block was distal to the common lymphoid progenitor in transgenic mice. GATA2 appeared to induce growth via downstream activation of Nmyc and Hoxa9. Our results demonstrate that GATA2 overexpression at low level confers self-renewal capacity to myeloid progenitors and is relevant to myeloid leukemia development.