Comparative analysis of genes regulated by PML/RARα and PLZF/RARα response to retinoic acid using oligonucleotide arrays

Acute promyelocytic leukemia (APL) is associated with chromosomal translocations involving retinoic acid receptor alpha (RARalpha) and its fusion partners including promyelocytic leukemia (PML) and promyelocytic leukemia zinc finger (PLZF). Using oligonucleotide arrays, we examined changes in global gene expression mediated by the ectopic expression of either PML/RARalpha (retinold-sensitive) or PLZF/ RARalpha (retinoid-resistant) in U937 cells. Of more than 5000 genes analyzed, 16 genes were commonly up-regulated, and 57 genes were down-regulated by both fusion proteins suggesting their role in the APL phenotype. In our APL model, for example, TNFAIP2, TNFR2, ELF4, RARgamma, and HoxA1 were down-regulated by both fusion proteins in the absence of retinoic acid (RA). RA strongly up-regulated these genes in PML/RARalpha, but not in PLZF/ RARalpha 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 tumor necrosis factor alpha (TNFalpha) 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 that cooperation between the RA and TNFalpha 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. (C) 2003 by The American Society of Hematology.