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

Abstract

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 35S-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.

Biosystem Analysis of the Hypoxia Inducible Domain Family Member 2A: Implications in Cancer Biology

“…It proposes that HK2 is a vital metabolic driver of DLBCL (Diffuse Large B-cell Lymphoma) phenotype. The authors contributed to the public dataset GSE104212 [18]. For this study, two human lymphoma cell lines, HLY-1 and SUDHL2, were cultured and assessed under hypoxic conditions (n = 3, biological replicates per cell line) or normoxia (n = 3, biological replicates per cell line), followed by a gene expression microarray analysis to examine the global gene expression differences under these conditions [18].…”

“…The authors contributed to the public dataset GSE104212 [18]. For this study, two human lymphoma cell lines, HLY-1 and SUDHL2, were cultured and assessed under hypoxic conditions (n = 3, biological replicates per cell line) or normoxia (n = 3, biological replicates per cell line), followed by a gene expression microarray analysis to examine the global gene expression differences under these conditions [18]. Another dataset analyzed was obtained with the Agilent-014850 Whole Human Genome Microarray 4 × 44K G4112F and were used in the study of gene-expression profiles in a series of non-Hodgkin lymphoma (NHL) patients (Dataset GSE32018).…”

“…Bhalla et al (2018) [18] studied the role of hypoxia in DLBCL using two human lymphoma cell lines, HLY-1 and SUDHL2, which were cultured under conditions of hypoxia or normoxia. In this study, a gene expression microarray analysis was employed to examine the global gene expression differences under these conditions.…”

“…Neither of the two cell lines displayed differential expression of the HIGD2A gene in response to hypoxia ( Figure 7A). Bhalla et al (2018) [18] suggested that the growth of lymphoma cell lines HLY-1 and SUDHL2 was resistant to hypoxic stress. Gómez-Abad et al, (2011) [19] also studied the gene-expression profile in a series of non-Hodgkin lymphoma patients, Follicular Lymphoma (FL), Marginal Zone Lymphoma_Type (MALT), Nodal Marginal Zone Lymphoma (NMZL), Diffuse Large B Cell Lymphoma (DLBCL), Mantle Cell Lymphoma (MCL), Chronic Lymphocytic Leukemia (CLL) and as controls, reactive tonsils, and lymph-node were used.…”

Hexokinase 2 displacement from mitochondria-associated membranes prompts Ca2+-dependent death of cancer cells

“…During the neoplastic process, metabolic changes are required to allow cell growth in conditions of fluctuating nutrient and oxygen availability (Vander Heiden & DeBerardinis, 2017). HK2 plays a major role in this metabolic rewiring (DeWaal et al, 2018;Robey & Hay, 2006;Wang et al, 2014), being induced by oncogenic K-Ras activation (Patra et al, 2013) or in response to (pseudo)hypoxia (Bhalla et al, 2018;Semenza, 2013). HK2 is mainly bound to the outer mitochondrial membrane, where it can gain privileged access to newly synthesized ATP, thus increasing efficiency in glucose usage (Mathupala et al, 2009), while following glucose deprivation HK2 elicits autophagy by inhibiting mTORC1 (Roberts et al, 2014).…”