Novel Biomarker Proteins in Chronic Lymphocytic Leukemia: Impact on Diagnosis, Prognosis and Treatment

Abstract

In many cancers, cells undergo re-programming of metabolism, cell survival and anti-apoptotic defense strategies, with the proteins mediating this reprogramming representing potential biomarkers. Here, we searched for novel biomarker proteins in chronic lymphocytic leukemia (CLL) that can impact diagnosis, treatment and prognosis by comparing the protein expression profiles of peripheral blood mononuclear cells from CLL patients and healthy donors using specific antibodies, mass spectrometry and binary logistic regression analyses and other bioinformatics tools. Mass spectrometry (LC-HR-MS/MS) analysis identified 1,360 proteins whose expression levels were modified in CLL-derived lymphocytes. Some of these proteins were previously connected to different cancer types, including CLL, while four other highly expressed proteins were not previously reported to be associated with cancer, and here, for the first time, DDX46 and AK3 are linked to CLL. Down-regulation expression of two of these proteins resulted in cell growth inhibition. High DDX46 expression levels were associated with shorter survival of CLL patients and thus can serve as a prognosis marker. The proteins with modified expression include proteins involved in RNA splicing and translation and particularly mitochondrial proteins involved in apoptosis and metabolism. Thus, we focused on several metabolism- and apoptosis-modulating proteins, particularly on the voltage-dependent anion channel 1 (VDAC1), regulating both metabolism and apoptosis. Expression levels of Bcl-2, VDAC1, MAVS, AIF and SMAC/Diablo were markedly increased in CLL-derived lymphocytes. VDAC1 levels were highly correlated with the amount of CLL-cancerous CD19+/CD5+ cells and with the levels of all other apoptosis-modulating proteins tested. Binary logistic regression analysis demonstrated the ability to predict probability of disease with over 90% accuracy. Finally, based on the changes in the levels of several proteins in CLL patients, as revealed from LC-HR-MS/MS, we could distinguish between patients in a stable disease state and those who would be later transferred to anti-cancer treatments. The over-expressed proteins can thus serve as potential biomarkers for early diagnosis, prognosis, new targets for CLL therapy, and treatment guidance of CLL, forming the basis for personalized therapy.

Identifying novel cell glycolysis related gene signature predictive of overall survival in bladder urothelial carcinoma

“…AK3 compounds are blockers of mitosis, which block the proliferation and apoptosis of the cells in colonic and breast cancers. AK3 upregulation positively correlates with the overall survival of patients with colonic cancer and breast cancer [17][18], AK3 downregulation can lead to severe inhibition of the growth of the cancer cells in chronic lymphocytic leukemia [19], which is in line with our nding that AK3 is a protective type mRNA. NUP188 is a nucleoporin regulating chromosome segregation and promotes tumor cell division and growth by participating in mitotic process.…”

Voltage-Dependent Anion Channel 1 As an Emerging Drug Target for Novel Anti-Cancer Therapeutics

“…Similar results were obtained in other studies of breast, colon, liver, lung, pancreatic, and thyroid cancers ( 249 ) and lung tumors ( 256 ). VDAC1 was also found to be overexpressed in peripheral blood mononuclear cells (PBMCs) from chronic lymphocytic leukemia (CLL) patients, as compared to PBMCs from healthy donors ( 257 ). Cervical cancer patients with high VDAC1 displayed higher rates of recurrence and poorer overall survival than those with low VDAC1 ( 258 ).…”

Biomarkers in Stress Related Diseases/Disorders: Diagnostic, Prognostic, and Therapeutic Values

“…Biomarkers have been identified for various diseases and disorders; for example, metabolic disorders (Boenzi and Diodato, 2018), cardiovascular disease (Ho et al, 2018), myocardial infarctions (Ge et al, 2018), gynecological diseases (Flores et al, 2018; Liu et al, 2018), neurological disorders (Lashley et al, 2018) and hepatic diseases (Wallace et al, 2016; Raghu et al, 2018). In the present era of high cancer prevalence, sensitive neoplastic biomarkers are a significant research focus, which could aid the early detection and prognosis of neoplastic changes (Tainsky, 2009; Admoni-Elisha et al, 2016; Andersen et al, 2017; Liu et al, 2018). In addition to conventional biomarkers, advances in molecular medicine have identified cell-free nucleic acids, including DNA, mRNA, and microRNAs (miRNAs) as potential markers for several diseases (Lo et al, 2007; Swarup and Rajeswari, 2007; Gilad et al, 2008; Shen et al, 2016; Hibner et al, 2018; Lin et al, 2018).…”