Genetic methylation and lymphoid malignancies: biomarkers of tumor progression and targeted therapy
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REVIEW
Open Access
Genetic methylation and lymphoid malignancies: biomarkers of tumor progression and targeted therapy Xia Zhao1,2, Wei Zhang1, Li Wang1,2 and Wei-Li Zhao1,2*
Abstract Lymphoid malignancies, mainly including lymphocytic leukemia and lymphoma, are a group of heterogeneous diseases. Although the clinical outcome of patients has been significantly improved with current immuno-chemotherapy, definitive biomarkers remain to be investigated, particularly those reflecting the malignant behavior of tumor cells and those helpful for developing optimal targeted therapy. Recently, genome-wide analysis reveals that altered genetic methylations play an important role in tumor progression through regulation of multiple cellular transduction pathways. This review describes the pathogenetic effect of the aberrant genetic methylation in lymphoid malignancies, with special emphasis on potential therapeutic strategies targeting key signaling networks. Keywords: Methylation, Leukemia, Lymphoma, Biomarker, Targeted therapy
Introduction Lymphoid malignancies, mainly including lymphocytic leukemia and lymphoma, are a group of disorders that originate from neoplastic transformation of lymphocytes. Diseases vary in cells of origin, histologic appearances, molecular biology, clinical features and disease prognosis. Thus, searching for biomarkers closely related to tumor progression is critical to better understand the disease pathogenesis and to develop subsequent targeted therapy. DNA methylation plays a pivotal role in transcriptional regulation. Aberrant promoter hypermethylation has been observed in cancer cells, which is responsible for the transcriptional silencing of tumor suppressor genes [1,2]. For example, tumor suppressor genes, such as p15 (CDKN2B) [3], p16 (CDKN2A) [4], p57 (CDKN1C) [5], p73 (TP73) [6], SHP-1 [7] and DAPK [8], are frequently hypermethylated and related to tumor progression in lymphoid malignancies. In this review, we described recent advances on alterations of genetic methylation profiling in lymphoid malignancies and highlighted their effects on specific signaling * Correspondence: [email protected] 1 State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Er Road, Shanghai 200025, China 2 Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai, China
pathways involved in disease progression, which may be helpful in identifying strategies of targeted therapy. Part I: Genome-wide methylation in lymphoid malignancies Acute lymphoblastic leukemia (ALL)
Acute lymphoblastic leukemia (ALL) is derived from malignant proliferation of immature lymphoblast cells committed to B- or T-cell lineage. They are the most common, and some of the most curable, tumors in children. ALL has lower prevalence in adults. However, patients usually have much poorer disease outcome. In T-ALL, methylation pattern of 27 T-ALL-related genes were assessed
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