ABSTRACT Progranulin (pgrn) (granulin-epithelin precursor, PC-cell derived growth factor or acrogranin) is a multifunctional secreted glycoprotein implicated in tumorigenesis, development, inflammation and repair. It is highly expressed in macrophage and monocyte-derived dendritic cells. Here we investigate its regulation in myeloid cells. All-trans-retinoic acid (ATRA) increased pgrn mRNA levels in myelomonocytic cells (CD34+ progenitors; monoblastic U937; monocytic THP-1; progranulocytic HL-60; macrophage RAW264.7) but not in non-myeloid cells tested. Interleukin-4 impaired basal expression of pgrn in U937. Differentiation agents dimethylsulfoxide (DMSO), and, in U937 only, phorbol ester (PMA) elevated pgrn mRNA expression late in differentiation, suggestive of roles for pgrn in more mature terminally differentiated granulocyte/monocytes, rather than during growth or differentiation. The response of pgrn mRNA to ATRA differs in U937 and HL-60 lineages. In U937, ATRA and chemical differentiation agents greatly increased pgrn mRNA stability, while in HL-60, ATRA accelerated pgrn mRNA turnover. The initial upregulation of pgrn mRNA after stimulation with ATRA was independent of de novo protein synthesis in U937, but not HL-60. Chemical blockade of NF-B activation impaired ATRA stimulated pgrn expression in HL-60, but not U937, while in U937 it blocked PMA-induced pgrn mRNA expression, suggestive of cell-specific roles for NF-B in determining pgrn mRNA levels. We propose that: (i) ATRA regulates pgrn mRNA levels in myelomonocytic cells; (ii) ATRA acts in a cell-specific manner involving the differential control of mRNA stability and differential requirement for NF-B signaling; (iii) elevated pgrn mRNA expression is characteristic of more mature cells, and does not stimulate differentiation.