Abstract
Simple SummaryDespite continued efforts, the current status of knowledge in CLL molecular pathobiology, diagnosis, prognosis and treatment remains elusive and imprecise. Proteomics approaches combined with advanced bioinformatics and drug repurposing promise to shed light on the complex proteome heterogeneity of CLL patients and mitigate, improve, or even eliminate the knowledge stagnation. In relation to this concept, this review presents a brief overview of all the available proteomics and drug repurposing studies in CLL and suggests the way such studies can be exploited to find effective therapeutic options combined with drug repurposing strategies to adopt and accost a more “precision medicine” spectrum.CLL is a hematological malignancy considered as the most frequent lymphoproliferative disease in the western world. It is characterized by high molecular heterogeneity and despite the available therapeutic options, there are many patient subgroups showing the insufficient effectiveness of disease treatment. The challenge is to investigate the individual molecular characteristics and heterogeneity of these patients. Proteomics analysis is a powerful approach that monitors the constant state of flux operators of genetic information and can unravel the proteome heterogeneity and rewiring into protein pathways in CLL patients. This review essences all the available proteomics studies in CLL and suggests the way these studies can be exploited to find effective therapeutic options combined with drug repurposing approaches. Drug repurposing utilizes all the existing knowledge of the safety and efficacy of FDA-approved or investigational drugs and anticipates drug alignment to crucial CLL therapeutic targets, leading to a better disease outcome. The drug repurposing studies in CLL are also discussed in this review. The next goal involves the integration of proteomics-based drug repurposing in precision medicine, as well as the application of this procedure into clinical practice to predict the most appropriate drugs combination that could ensure therapy and the long-term survival of each CLL patient.
Highlights
Somatic mutations in immunoglobulin heavy chain variable region gene (IGHV), activating B cell receptor (BCR)-signaling kinases lead to the lower survival and proliferation of CLL cells, providing patients with “mutated” M-CLL, which is a better clinical outcome vs. “unmutated” U-CLL patients [2,9]
Prieto et al investigated the plasma-derived exosomes secreted in CLL, which in turn participate in the continuous crosstalk between the tumoral cells and their microenvironment [81]. They studied the proteomic profile of exosomes from five patients with progressive disease and five patients with indolent disease, both at the onset of disease and during its progression. They highlighted networks specific for leukemia progression related to cell infiltration, tumor proliferation, the PI3K/AKT pathway, survival and apoptosis, inflammation, and oxidative stress, and they focused on the proteins S100-A9 and junction plakoglobin (JUP), activators of the NF-κB and Wnt pathway, respectively
Khodadoust et al investigated tumor-derived class I (MHC-I) and II (MHC-II) antigen-presentation profiling of six follicular lymphoma (FL), one DLBCL, and two CLL samples, using immunoprecipitation followed by mass spectrometry (MS) [93]. They found the presentation of the clonal immunoglobulin molecule, including neoantigens by both class I and class II MHC, though more commonly in class II MHC. These findings suggested that immunoglobulin neoantigens are presented across most subtypes of B cell lymphomas and these neoantigens could become possible targets in immunotherapies
Summary
CLL is the most frequent lymphoproliferative disease in the western world [1,2] characterized by the clonal proliferation and progressive accumulation of mature, typically CD5-positive B-cells in the blood, bone marrow, and secondary lymphoid tissues [2,3,4] It shows a high biological, genetical, molecular and clinical diversity [1,5], projecting its highly heterogenous pathophysiology (Figure 1, Table S1). A plethora of pharmacological targets have been investigated in CLL (Table S2, Figure S1) Patients, according to their clinical history, are prioritized to therapeutic options, including chemotherapy, immunotherapy (IT), chimeric antigen receptor and other targeted therapeutic strategies, used alone or in combination. Among the promising CLL therapies under investigation targeting several deregulated pathways are the cross-talk between CLL cells, the tumor microenvironment [42,43], the Wnt signaling pathway [44], various miRNAs [45], the Notch signaling pathway [46], the mitochondrial metabolism [16] and the epigenetic modifications [47]
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