Human Gene Set: PARK_APL_PATHOGENESIS_DN


Standard name PARK_APL_PATHOGENESIS_DN
Systematic name M2541
Brief description Genes down-regulated in U937 cells (acute promyelocytic leukemia, APL) expressing RARA [GeneID=5914] fused with either PML or PLZF [GeneID=5371;7704].
Full description or abstract Acute promyelocytic leukemia (APL) is associated with chromosomal translocations involving retinoic acid receptor alpha (RAR alpha) 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/RAR alpha (retinoid-sensitive) or PLZF/RAR alpha (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, RAR gamma, and HoxA1 were down-regulated by both fusion proteins in the absence of retinoic acid (RA). RA strongly up-regulated these genes in PML/RAR alpha, but not in PLZF/RAR alpha 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 (TNF alpha) 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.
Collection C2: Curated
      CGP: Chemical and Genetic Perturbations
Source publication Pubmed 12893766   Authors: Park DJ,Vuong PT,de Vos S,Douer D,Koeffler HP
Exact source Table 1: Down-regulated gene
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Source species Homo sapiens
Contributed by Arthur Liberzon (MSigDB Team)
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identifier namespace		 AFFY_HuGene
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