Negative regulation of granulocytic differentiation in the myeloid precursor cell line 32Dcl3 by ear-2, a mammalian homolog of Drosophila seven-up, and a chimeric leukemogenic gene, AML1/ETO(MTG8)

Abstract

The polyomavirus enhancer binding protein 2 alpha B (AML1/PEBP2 alpha B/Cbfa2) plays a pivotal role in granulocyte colony-stimulating factor (G-CSF)-mediated differentiation of a myeloid progenitor cell line, 32Dc13. In this article, we report the identification of a PEBP2 alpha B interacting protein, Ear-2. an orphan member of the nuclear hormone receptor superfamily that directly binds to and can inhibit the function of PEBP2 alpha B, Ear-2 is expressed in proliferating 32Dc13 cells in presence of interleukin 3 but is down-regulated during differentiation induced by G-CSF, Interestingly, AML1/ETO(MTG8), a leukemogenic chimeric protein can block the differentiation of 32Dc13 cells, which is accompanied by the sustained expression of ear-2. Overexpression of Ear-2 can prevent G-CSF-induced differentiation, strongly suggesting that ear-2 is a key negative regulator of granulocytic differentiation, Our results indicate that a dynamic balance existing between PEBP2 alpha B and Ear-2 appears to determine the choice between growth or differentiation for myeloid cells.