Comparative Analysis of Genes Regulated by PML/RARα and PLZF/RARα in Response to Retinoic Acid Using Oligonucleotide Arrays

Acute promyelocytic leukemia (APL) is associated with chromosomal translocations involving RAR and its fusion partners including PML and PLZF. Using oligonucleotide arrays, we examined changes in global gene expression mediated by the ectopic expression of either PML/RAR (retinoid-sensitive) or PLZF/RAR (retinoid-resistant) in U937 cells. Of over 5000 genes analyzed, 16 genes were commonly upregulated, and 57 genes were downregulated by both fusion proteins suggesting their role in the APL phenotype. In our APL model, for example, TNFAIP2, TNFR2, ELF4, RAR, and HoxA1 were downregulated by both fusion proteins in the absence of RA. RA strongly upregulated these genes in PML/RAR, but not in PLZF/RAR expressing U937 cells. Expression studies in NB4, retinoid-resistant NB4-R2, normal human CD34 + cells, and APL patient samples strongly suggest their role in the regulation of granulocytic differentiation. Furthermore, combined treatment with TNF and RA synergistically enhanced granulocytic differentiation in NB4 cells but not in NB4-R2 cells. Our data indicate that APL pathogenesis and retinoid-induced granulocytic differentiation of APL cells involve genes in the cell death pathway, and cooperation between the RA and TNF signaling pathways exists. Targeting both the retinoid-dependent differentiation and the cell death pathways may improve leukemic therapy, especially in retinoid-resistant acute myeloid leukemia.