Glycolytic biomarkers predict transformation in patients with follicular lymphoma

Abstract

Follicular lymphoma (FL) is an indolent neoplasia comprising approximately 20% of lymphomas. FL is generally considered incurable, with a median survival exceeding 10 years. A subset of FL patients experiences histological transformation (HT) to a more aggressive lymphoma, resulting in markedly poorer clinical outcome, with a reduced median survival after transformation of 1-2 years. Early, reliable prediction of HT would be valuable in the clinical setting, allowing pre-emptive therapeutic intervention. We previously used proteomics to identify the glycolytic enzymes fructose-bisphosphate aldolase A (aldolase A) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as candidate predictors of FL transformation. Now, we use immunohistochemistry to evaluate expression of these enzymes in paired primary FLs from patients with (n = 41) or without subsequent HT (n = 49), to test their value as predictive biomarkers. At initial FL diagnosis, patients with subsequent HT had significantly higher expression of aldolase A and GAPDH (p<0.001 and p<0.01) compared with patients without HT. Furthermore, high expression of aldolase A and GAPDH was associated with significantly shorter transformation free survival (p = 0.018, p = 0.001). These data suggest that high expression of aldolase A and GAPDH, may indicate increased metabolic turnover, and that these enzymes may be useful biomarkers in primary FL for predicting the risk of subsequent lymphoma transformation.

Linking Immunoevasion and Metabolic Reprogramming in B-Cell–Derived Lymphomas

“…Beyond that, metabolism of FLs remains largely unexplored. Notably, transformation into DLBCL is associated with an enhanced expression of the glycolytic machinery, which is in line with the increased glucose uptake as revealed by 18 F-FDG PET/CT in transformed lymphomas ( 27 , 28 ).…”

“…The most studied example of nutrient competition is the increased glucose consumption by malignant cells caused by elevated expression levels of glucose transporters and enzymes of the glycolytic machinery {as seen in BCR-DLBCL [e.g., GAPDH expression ( 52 ) and lactate secretion ( 13 )], transformed FL [e.g., GAPDH and aldolase A ( 27 , 28 )], MCL [e.g., glycolytic flux ( 33 )], and CLL in the LN-/BM-niche [e.g., glycolytic flux and key glycolytic enzymes ( 44 )]}. This is detrimental for T- and NK-cells as their proliferation, activation, and differentiation is highly dependent on glucose as a fuel for both aerobic glycolysis and OxPhos [reviewed in ( 53 )].…”

“…Tumors including B-cell malignancies have developed a variety of mechanisms to evade the anti-tumor immunity. Amongst others, four major "metabolic strategies" have been identified (Figure 2): 1) competition over nutrients, 2) production of bioactive metabolites, 3) induction/promotion of regulatory, tolerogenic immune cells, and 4) metabolic control of immune checkpoints (ICPs).The most studied example of nutrient competition is the increased glucose consumption by malignant cells caused by elevated expression levels of glucose transporters and enzymes of the glycolytic machinery {as seen in BCR-DLBCL [e.g., GAPDH expression (52) and lactate secretion(13)], transformed FL [e.g., GAPDH and aldolase A(27,28)], MCL [e.g., glycolytic flux (33)], and CLL in the LN-/BM-niche [e.g., glycolytic flux and key glycolytic enzymes(44)]}. This is detrimental for T-and NK-cells as their proliferation, activation, and differentiation is highly dependent on glucose as a fuel for both aerobic glycolysis and OxPhos [reviewed in(53)].…”

PD-1 Expression in Pre-Treatment Follicular Lymphoma Predicts the Risk of Subsequent High-Grade Transformation

“…These clinical data as well as immunohistochemical data on other putative biological markers in this cohort have previously been published. 7 , 11 , 12 The study is approved by the Danish National Committee on Health Research Ethics (1-10-72-276-13) and the Danish Data Protection Agency (1-16-02-407-13). The requirement for study-specific informed consent was waived due to the retrospective nature of the study and the long follow-up time since inclusion.…”

“…Biomarkers that could reliably predict HT, and thus identify patients at increased risk of transformation, would be highly valuable in the clinical setting. To date, both clinical features and biological markers have been investigated as possible risk factors for HT, 7 , 8 , 11 , 12 but no definitive biomarkers of transformation have yet been identified. Known factors associated with poor prognosis in FL include advanced Ann Arbor stage, elevated lactate dehydrogenase (LDH), B-symptoms as well as a high Follicular Lymphoma International Prognostic Index (FLIPI) score.…”