Identification of an interleukin-3-regulated aldoketo reductase gene in myeloid cells which may function in autocrine regulation of myelopoiesis

The EML hematopoietic progenitor cell line is a model system for studying m olecular events regulating myeloid commitment and terminal differentiation. We used representational difference analysis to identify genes that are ex pressed differentially during myeloid differentiation of EML cells. One gen e (named mAKRa) encoded a novel member of the aldoketo reductase (AKR) supe rfamily of cytosolic NAD(P)(H)-dependent oxidoreductases. mAKRa mRNA was de tected in murine hematopoietic tissues including bone marrow, spleen, and t hymus. In myeloid cell lines, mAKRa was expressed at highest levels in cell s representative of promyelocytes. mAKRa mRNA levels increased rapidly in r esponse to interleukin-3 over the first 24 h of EML cell differentiation wh en the cells undergo lineage commitment and extensive proliferation, mAKRa mRNA levels decreased later in the differentiation process particularly whe n the EML cells were cultured with granulocyte/macrophage colony-stimulatin g factor and retinoic acid to induce terminal granulocytic maturation. mAKR a mRNA levels decreased during retinoic acid-induced terminal granulocytic differentiation of the MPRO promyelocyte cell line. AKRs act as molecular s witches by catalyzing the interconversion or inactivation of bioactive mole cules including steroids and prostaglandins. We propose that mAKRa may cata lyze the production or catabolism of autocrine factors that promote the pro liferation and/or lineage commitment of early myeloid progenitors.