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Published molecular profiling studies in patients with lymphoma suggested the influence of hypoxia inducible factor-1 alpha (HIF1α) targets in prognosis of DLBCL. Yet, the role of hypoxia in hematological malignancies remains unclear. We observed that activation of  HIF1α  resulted in global translation repression during hypoxic stress in DLBCL. Protein translation efficiency as measured using  35 S-labeled methionine incorporation revealed a ≥50% reduction in translation upon activation of HIF1α. Importantly, translation was not completely inhibited and expression of clinically correlated hypoxia targets such as  GLUT1 ,  HK2 , and  CYT-C  was found to be refractory to translational repression under hypoxia in DLBCL cells. Notably, hypoxic induction of these genes was not observed in normal primary B-cells. Translational repression was coupled with a decrease in mitochondrial function. Screening of primary DLBCL patient samples revealed that expression of  HK2 , which encodes for the enzyme hexokinase 2, was significantly correlated with DLBCL phenotype. Genetic knockdown studies demonstrated that  HK2  is required for promoting growth of DLBCL under hypoxic stress. Altogether, our findings provide strong support for the direct contribution of  HK2  in B-cell lymphoma development and suggest that  HK2  is a key metabolic driver of the DLBCL phenotype.

Role of hypoxia in Diffuse Large B-cell Lymphoma: Metabolic repression and selective translation of HK2 facilitates development of DLBCL