Hypoxia inducible factor-alpha activation in lymphoma and relationship to the thioredoxin family.

Hypoxia-Inducible-Factors (HIFs) activate oncogenic pathways, while thioredoxins, including thioredoxin-1 (Trx1) and thioredoxin reductases-1 and -2 (TrxR1 and TrxR2), promote HIF-α stabilization. Elevated levels of thioredoxin or HIF have been associated with poor outcomes in solid tumors and each represent potential therapeutic targets. In lymphoma cell line immunoblotting studies, we found that Raji and SUDHL4 cells exhibited normoxic HIF-2α protein-stabilization. Furthermore, five lymphoma cell-lines showed increased TrxR1 expression, while only Namalwa, HF1, and SUDHL4 had Trx1 and TrxR2 activation. Utilizing tissue microarrays from diffuse large B-cell (DLBCL) and follicular lymphoma (FL) patient specimens (n=82), we found different frequency of HIF expression in FL versus DLBCL as well as differing HIF-1 versus HIF-2 expression within each histologic subgroup. Forty-four percent of DLBCL versus 11% of FL cases had moderate-to-high expression of both HIF-1α and HIF-2α (p=0.0017), while 56% of DLBCL and 32% of FL samples had at least low HIF-1α and HIF-2α expression (p=0.042). Survival analysis among newly-diagnosed DLBCL cases showed 44% 2-year event-free survival (EFS) and 67% overall survival (OS) with high HIF-1α and HIF-2α expression compared with 67% and 76%, respectively, (p=0.10 and p=0.64, respectively) without high expression. These data demonstrate that HIF and the thioredoxins are activated in lymphoma and that HIF expression may influence prognosis.