IRF4 may represent a therapeutic target in ATL because ATL cells select for a mutant of IRF4 with higher nuclear expression and transcriptional activity, and overexpression of IRF4 induces the expansion of T lymphocytes <i>in vivo</i>.
We have examined the specific mechanisms underlying the expression and regulation of the IRF-4 transcription factor in HTLV-I-infected cells and have shown that constitutive IRF-4 expression is exclusive to the transformed, leukemic ATL phenotype as opposed to the nonleukemic HTLV-I associated myelopathies/tropical spastic paraparesis (HAM/TSP) phenotype.
In vivo and in vitro analyses have identified several regulatory regions within the human IRF-4 promoter that interact with the transcriptional regulators NF-kappaB, NF-AT, and Sp-1 to drive IRF-4 production in HTLV-I-infected, ATL-derived cells. cDNA array analysis of an IRF-4-expressing T cell line has also provided valuable insight into potential IRF-4 target genes.
All HTLV-1 infected cell lines and ATL patient lymphocytes demonstrated a dramatic decrease in cyclin B1 levels; subsequent analysis of the cyclin B1 promoter identified two sites important in IRF-4 binding and repression of cyclin B1 expression.
Taken together, our results indicate that IRF4 is involved in the pathogenesis of ATL through its positive effect on the cell cycle, and that IRF4 can be used as a molecular marker of clinical subtype in ATL.