Proteomics identifies apoptotic markers as predictors of histological transformation in patients with follicular lymphoma

Abstract

Follicular lymphoma (FL) is an indolent lymphoma with a generally favorable prognosis. However, histological transformation (HT) to a more aggressive disease leads to markedly inferior outcomes. This study aimed to identify biological differences predictive of HT at the time of initial FL diagnosis. We show differential protein expression between diagnostic tumor-tissue samples from FL patients with subsequent HT (subsequently-transforming FL, st-FL, n=20) compared with patients without HT (non-transforming FL, nt-FL, n=34) by label-free quantification nano liquid chromatography-tandem mass spectrometry (LFQ nLC-MS/MS) analysis. Protein profiles from nt-FL and st-FL samples identified patients with high risk of HT. This was accompanied by disturbances in cellular pathways influencing apoptosis, the cytoskeleton, cell cycle, and immune processes. Comparisons between diagnostic st-FL samples and paired transformed FL (tFL, n=20) samples demonstrated differential protein profiles and disrupted cellular pathways, indicating striking biological differences from the time of diagnosis up to HT. Immunohistochemical analysis of apoptotic proteins, CASP3, MCL1, BAX, BCL-xL, and BCL-rambo, confirmed higher expression levels in st-FL compared with nt-FL samples (p<0.001, p=0.015, p=0.003, p=0.025, and p=0.057, respectively). Moreover, all five markers were associated with shorter transformation-free survival (TFS; p<0.001, p=0.002, p<0.001, p=0.069, and p=0.010, respectively). Notably, combining the expression levels of these proteins in a risk score revealed increasingly inferior TFS with an increasing number of positive markers. In conclusion, proteomics identified altered protein expression profiles (in particular apoptotic proteins) at time of FL diagnosis, that predicted later transformation. This may contribute to future improved risk assessment and personalized management strategies for these patients.

Characterization of Human B Cell Hematological Malignancies Using Protein-Based Approaches

“…Recently, Label-Free Quantification (LFQ) nLC-MS/MS analysis has shown differential protein expression between FL samples from patients with subsequent HT compared to patients without HT, revealing protein patterns associated with a high risk of HT. Notably, IHC analysis confirmed higher expression levels of apoptotic proteins such as CASP3, MCL1, BAX, BCL-xL, and BCL-Rambo in transforming FL [94].…”

“…Proteomic analyses have also revealed potential predictive indicators of histological transformation (HT) in FL [94]. Recently, Label-Free Quantification (LFQ) nLC-MS/MS analysis has shown differential protein expression between FL samples from patients with subsequent HT compared to patients without HT, revealing protein patterns associated with a high risk of HT.…”