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

Autor: Anna Melkov, Lee Admoni-Elisha, Varda Shoshan-Barmatz, Ori Zelichov, Itai Levi, Itay Nakdimon, Tasleem Arif, Tal Prezma, Anna Shteinfer, Nir Arbel
Rok vydání: 2015
Předmět:
0301 basic medicine
Male
Proteome
Chronic lymphocytic leukemia
Protein Expression
Protein metabolism
Cancer Treatment
lcsh:Medicine
Apoptosis
Biochemistry
Hematologic Cancers and Related Disorders
chemistry.chemical_compound
Tandem Mass Spectrometry
hemic and lymphatic diseases
Tumor Cells
Cultured
Medicine and Health Sciences
Small interfering RNAs
lcsh:Science
Energy-Producing Organelles
Protein Metabolism
Chronic Lymphoblastic Leukemia
Multidisciplinary
Cell Death
Reverse Transcriptase Polymerase Chain Reaction
Hematology
Prognosis
Mitochondria
Nucleic acids
Leukemia
Oncology
Cell Processes
Lymphoblastic Leukemia
Biomarker (medicine)
Female
Cellular Structures and Organelles
VDAC1
Research Article
Blotting
Western
Biology
Bioenergetics
Real-Time Polymerase Chain Reaction
Research and Analysis Methods
03 medical and health sciences
Leukemias
medicine
Biomarkers
Tumor
Gene Expression and Vector Techniques
Genetics
Humans
RNA
Messenger
Molecular Biology Techniques
Non-coding RNA
Molecular Biology
Aged
Molecular Biology Assays and Analysis Techniques
lcsh:R
Cancer
Biology and Life Sciences
Cancers and Neoplasms
Cell Biology
medicine.disease
Leukemia
Lymphocytic
Chronic
B-Cell
Gene regulation
030104 developmental biology
Metabolism
chemistry
Immunology
Leukocytes
Mononuclear
RNA
lcsh:Q
Gene expression
CD5
Biomarkers
Chromatography
Liquid
Zdroj: PLoS ONE
PLoS ONE, Vol 11, Iss 4, p e0148500 (2016)
ISSN: 1932-6203
Popis: 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.
Databáze: OpenAIRE
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