Non-Hodgkin's lymphoma (NHL) is a cancer that starts in white blood cells called lymphocytes, which are part of the body's immune system. NHL most often affects adults, but children can get it too. Lymphoma affects the body's lymph system. The lymph system is part of the immune system, which helps fight infections and some other diseases. It also helps fluids move through the body.
Lymphomas can start anywhere in the body where lymph tissue is found. The major sites of lymph tissue include lymph nodes, spleen, bone marrow, thymus, adenoids and tonsils and digestive tract. Similar to other types of cancer, NHL arises by a multistep accumulation of genetic aberrations that induce a selective growth advantage of the malignant clone. Recurrent translocations, which occur during different steps of B-cell differentiation, are often an initial step in the malignant transformation.
In this article, we list part of these proteins involved in NHL based on the information provided by NCG (web resource to analyze duplicability, orthology and network properties of cancer genes).
B2M | BCL10 | BCL2 | BCL6 | BTG1 | BTG2 | CARD11 | CCND3 |
CD58 | CD70 | CD79B | CIITA | CREBBP | ETS1 | EZH2 | FAS |
FAT2 | FOXO1 | GNA13 | HIST1H1C | IRF4 | IRF8 | KLHL6 | KMT2D |
MEF2B | MYD88 | SGK1 | TMEM30A | TNFRSF14 | TP53 |
Here, we display several key targets involved in mechanism of NHL, including:
B2M (Beta 2 microglobulin), a component of class I major histocompatibilty complex (MHC), is a cell surface protein on many somatic cells including T and B lymphocytes and macrophages [1]. The data obtained by G. Gupta et al. shows that serum B2M test can be an important prognostic tool for assessment of treatment response in NHL patients, as serum levels were significantly higher in NHL patients. Further, as B2M levels were also correlated with advanced stage, they may reflect the total amount or turnover of malignant cells in the body. Therefore, repeated determinations of serum B2M in these patients might be useful as an estimate of the residual malignant cell mass after therapy [2].
BCL10 (B-cell lymphoma/leukemia 10) is an N-terminal CARD (Caspase Recruitment Domain) containing protein that is involved in the adaptive immune response. Like BCL2, BCL3, BCL5, BCL6, BCL7A, and BCL9, it has clinical significance in lymphoma. Mutations in the gene can lead to lymphoma, mucosa-associated lymphoid type. Wild-type BCL10 promoted apoptosis and suppressed malignant transformation in vitro, whereas truncated mutants lost the pro-apoptotic activity and exhibited gain of function enhancement of transformation [3].
BTG1 (BTG Anti-Proliferation Factor 1) is a member of the TOB/BTG protein family, which is a transducer of ErbB-2 and TOB2. It is characterised by the conserved amino-terminal BTG domain, which mediates interactions with the human Caf1 (hCaf1) catalytic subunit of the Ccr4-Not deadenylase complex [4]. Recently, mutations in BTG1 and BTG2 have been identified in approximately 10-15% of NHL cases. They are functionally significant and are likely to contribute to malignant transformation and tumour cell grow [5].
CARD11 (Caspase recruitment domain-containing protein 11) belongs to the membrane-associated guanylate kinase (MAGUK) family, a class of proteins that functions as molecular scaffolds for the assembly of multiprotein complexes at specialized regions of the plasma membrane. CARD11 is involved in the function of immune system cells called lymphocytes, particularly T cells and B cells. CARD11 is an important adapter protein downstream of protein kinase C in lymphocytes. After lymphocytes are stimulated through their antigen receptors, CARD11 associates with BCL-10 and MALT1 to activate the IKK complex, then stimulating NF-κB to translocate into the nucleus for gene transcription for lymphocyte activation and proliferation.
CCND3 (Cyclin D3) functions in the regulation of CDK kinases in the cell cycle. Emerging evidence implicates CCND3 as a dominant oncogene in the pathogenesis and transformation in several histologic subtypes of mature B-cell malignancies with t(6;14)(p21.1;q32.3) and suggests that CCND3 overexpression seen in about 10% of Diffuse large B cell lymphoma (DLBCL, the most common non-Hodgkin lymphoma (NHL)) cases may have a genetic basis [6] [7].
References
[1] Eugene McPherson, J. Ng, RPh, E. Hazel, P. Tassy. Beta-2 Microglobulin and Soluble Interleukin-2 Receptor Serum Levels Correlates with Human Immunodeficiency Virus Associated Non-Hodgkins Lymphoma-Diffuse Large B-Cell Lymphoma (HIV-NHL-DLBCL) [J]. Blood. 2005, 106 (11): 4675.
[2] G. Gupta, V.S. Ghalaut, V. Lokanathan, P. Sharma. rognostic significance of serum Beta 2 Microglobulin in Non Hodgkin Lymphoma (33P) [J]. Annals of Oncology. 2017, 28 (suppl_10): x7-x15.
[3] Ming-Qing Du, Huaizheng Peng, Hongxiang Liu et al. BCL10 gene mutation in lymphoma [J]. Blood. 2000, 95 (12): 3885–3890.
[4] Almasmoum, Hibah. Biochemical analysis of the BTG1 variants associated with Non-Hodgkin’s lymphoma. 2017. http://eprints.nottingham.ac.uk/id/eprint/47720
[5] Hibah Almasmoum, Nigel H. Russell, V. Functional Analysis of BTG1 and BTG2 Variants in Non-Hodgkin Lymphoma [J]. Blood. 2016. 128 (22): 1753.
[6] T Sonoki , L Harder, D E Horsman et al. Cyclin D3 is a target gene of t(6;14)(p21.1;q32.3) of mature B-cell malignancies [J]. Blood. 2001, 98(9):2837-44.
[7] Ryan D. Morin, Sarit Assouline, Miguel Alcaide et al. Genetic Landscapes of Relapsed and Refractory Diffuse Large B-Cell Lymphomas [J]. Clin Cancer Res. 2015, 22(9); 2290–300.
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