Cell-type-specific early response gene expression during plasmacytoid differentiation of human B lymphocytic leukemia...

Monoclonal B lymphocytes from B cell chronic lymphocytic leukemia (B-CLL) can be induced to undergo plasmacytoid differentiation in vitro by the phorbol ester, phorbol 12-myristate 13-acetate (PMA). By differential screening of a cDNA library derived from cells treated with phorbol ester we have isolated and characterised a set of early response genes (ERGs) displaying rapid transient up-regulation of expression in response to PMA. Cross-hybridisation studies showed that PMA probably induces the expression of over one hundred distinct genes, implying an ERG complexity comparable to that activated by mitogenic stimulation of fibroblasts and normal T lymphocytes. Of 13 genes analysed in detail, most were induced by PMA without a requirement for de novo protein synthesis, whilst nuclear run-on analysis showed that at least some of the more abundant classes of ERG were up-regulated through transcriptional mechanisms. In a proliferating variant B-CLL population, few differences in ERG expression were seen, suggesting that these genes are part of a gene regulatory pathway coupled to the differentiative rather than the proliferative response of B-CLL cells. However, studies in a range of cell types revealed a surprisingly diverse pattern of PMA-induced expression where most ERGs were relatively B-CLL-specific. This implies an extreme diversity of gene regulatory pathways activated in the primary response by phorbol ester generally and suggests that the onset of PMA-induced plasmacytoid differentiation of B-CLL cells is preceded by activation of a complex gene regulatory program that is largely unique to this maturation-arrested B cell.