Abnormal expression of A20 and its regulated genes in peripheral blood from patients with lymphomas

Cancer Cell International

Yangqiu Li³  Wenyu Li²  Huo Tan¹  Gengxin Luo³  Bo Li³  Xiuli Wu³  Lijian Yang³  Shaohua Chen³  Liang Wang⁴  Chunyan Wang¹  Yi Xu³  Lichan Liang⁵  Yan Xu³  Xu Wang³ 

[1] Centre of Oncology and Hematology, The First Affiliated Hospital of Guangzhou Medical College, Guangzhou 510230, China;Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou 510080, China;Institute of Hematology, Jinan University, Guangzhou 510632, China;Department of Oncology, First Affiliated Hospital, Jinan University, Guangzhou 510632, China;Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou 510632, China

关键词: T cell immunodeficiency;    NF-κB;    A20;    MALT1;    Gene expression;    Lymphoma;   

Others  :  792097
DOI  :  10.1186/1475-2867-14-36

 received in 2013-12-20, accepted in 2014-04-16,  发布年份 2014

【 摘 要 】

Background

Cell-mediated immunity is often suppressed in patients with hematological malignancies. Recently, we found that low T cell receptor (TCR)-CD3 signaling was related to abnormal expression of the negative regulator of nuclear factor kappa B (NF-κB) A20 in acute myeloid leukemia. To investigate the characteristics of T cell immunodeficiency in lymphomas, we analyzed the expression features of A20 and its upstream regulating factor mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1) and genes downstream of NF-κB in patients with different lymphoma subtypes, including T cell non-Hodgkin lymphoma (T-NHL), B cell non-Hodgkin lymphoma (B-NHL) and NK/T cell lymphoma (NK/T-CL).

Methods

Real-time PCR was used to determine the expression level of the MALT1, MALT-V1 (variant 1), A20 and NF-κB genes in peripheral blood mononuclear cells (PBMCs) from 24 cases with T-NHL, 19 cases with B-NHL and 16 cases with NK/T-CL, and 31 healthy individuals (HI) served as control.

Results

Significantly lower A20 and NF-κB expression was found in patients with all three lymphoma subtypes compared with the healthy controls. Moreover, the MALT1 expression level was downregulated in all three lymphoma subtypes. A significant positive correlation between the expression level of MALT1 and A20, MALT1-V1 and A20, MALT1-V1 and NF-κB, and A20 and NF-κB was found.

Conclusions

An abnormal MALT1-A20-NF-κB expression pattern was found in patients with lymphoma, which may result a lack of A20 and dysfunctional MALT1 and may be related to lower T cell activation, which is a common feature in Chinese patients with lymphoma. This finding may at least partially explain the molecular mechanism of T cell immunodeficiency in lymphomas.

【 授权许可】

   
2014 Wang et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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【 参考文献 】

• [1]Grulich AE, Vajdic CM, Cozen W: Altered immunity as a risk factor for non-Hodgkin lymphoma. Cancer Epidemiol Biomarkers Prev 2007, 16:405-408.
• [2]Jost PJ, Ruland J: Aberrant NF-kappaB signaling in lymphoma: mechanisms, consequences, and therapeutic implications. Blood 2007, 109:2700-2707.
• [3]Sissolak G, Sissolak D, Jacobs P: Human immunodeficiency and Hodgkin lymphoma. Transfus Apher Sci 2010, 42:131-139.
• [4]Tran H, Nourse J, Hall S, Green M, Griffiths L, Gandhi MK: Immunodeficiency-associated lymphomas. Blood Rev 2008, 22:261-281.
• [5]Hymowitz SG, Wertz IE: A20: from ubiquitin editing to tumour suppression. Nat Rev Cancer 2010, 10:332-341.
• [6]Staudt LM: Oncogenic activation of NF-kappaB. Cold Spring Harb Perspect Biol 2010, 2:a000109.
• [7]Coornaert B, Baens M, Heyninck K, Bekaert T, Haegman M, Staal J, Sun L, Chen ZJ, Marynen P, Beyaert R: T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-kappaB inhibitor A20. Nat Immunol 2008, 9:263-271.
• [8]Ruland J, Duncan GS, Wakeham A, Mak TW: Differential requirement for Malt1 in T and B cell antigen receptor signaling. Immunity 2003, 19:749-758.
• [9]Li S, Yang X, Shao J, Shen Y: Structural insights into the assembly of CARMA1 and BCL10. PLoS One 2012, 7:e42775.
• [10]Hara H, Iizasa E, Nakaya M, Yoshida H: L-CBM signaling in lymphocyte development and function. J Blood Med 2010, 1:93-104.
• [11]Thome M: Multifunctional roles for MALT1 in T-cell activation. Nat Rev Immunol 2008, 8:495-500.
• [12]Zhang F, Yang L, Li Y: The role of A20 in the pathogenesis of lymphocytic malignancy. Cancer Cell Int 2012, 12:44. BioMed Central Full Text
• [13]Chanudet E, Huang Y, Zeng N, Streubel B, Chott A, Raderer M, Du MQ: TNFAIP3 abnormalities in MALT lymphoma with autoimmunity. Br J Haematol 2011, 154:535-539.
• [14]Vereecke L, Beyaert R, van Loo G: The ubiquitin-editing enzyme A20 (TNFAIP3) is a central regulator of immunopathology. Trends Immunol 2009, 30:383-391.
• [15]Jaattela M, Mouritzen H, Elling F, Bastholm L: A20 zinc finger protein inhibits TNF and IL-1 signaling. J Immunol 1996, 156:1166-1173.
• [16]Tewari M, Wolf FW, Seldin MF, O’Shea KS, Dixit VM, Turka LA: Lymphoid expression and regulation of A20, an inhibitor of programmed cell death. J Immunol 1995, 154:1699-1706.
• [17]Krikos A, Laherty CD, Dixit VM: Transcriptional activation of the tumor necrosis factor alpha-inducible zinc finger protein, A20, is mediated by kappa B elements. J Biol Chem 1992, 267:17971-17976.
• [18]Tan H, Ye J, Luo X, Chen S, Yin Q, Yang L, Li Y: Clonal expanded TRA and TRB subfamily T cells in peripheral blood from patients with diffuse large B-cell lymphoma. Hematology 2010, 15:81-87.
• [19]Li Y: T-cell immunodeficiency and reconstruction based on TCR rearrangement analysis in hematological malignancy: update from 2011 ASH annual meeting. J Hematol Oncol 2012, 5:A3. BioMed Central Full Text
• [20]Li B, Liu S, Niu Y, Fang S, Wu X, Yu Z, Chen S, Yang L, Li Y: Altered expression of the TCR signaling related genes CD3 and FcepsilonRIgamma in patients with aplastic anemia. J Hematol Oncol 2012, 5:6. BioMed Central Full Text
• [21]Shi L, Chen S, Lu Y, Wang X, Xu L, Zhang F, Yang L, Wu X, Li B, Li Y: Changes in the MALT1-A20-NF-kappaB expression pattern may be related to T cell dysfunction in AML. Cancer Cell Int 2013, 13:37. BioMed Central Full Text
• [22]Zha X, Yan X, Shen Q, Zhang Y, Wu X, Chen S, Li B, Yang L, Geng S, Weng J, Du X, Li Y: Alternative expression of TCRzeta related genes in patients with chronic myeloid leukemia. J Hematol Oncol 2012, 5:74. BioMed Central Full Text
• [23]Ohm JE, Carbone DP: Immune dysfunction in cancer patients. Oncology (Williston Park) 2002, 16:11-18.
• [24]Li Y: Alterations in the expression pattern of TCR zeta chain in T cells from patients with hematological diseases. Hematology 2008, 13:267-275.
• [25]Chen S, Zha X, Yang L, Li B, Liye Z, Li Y: Deficiency of CD3gamma, delta, epsilon, and zeta expression in T cells from AML patients. Hematology 2011, 16:31-36.
• [26]Li Y, Yin Q, Yang L, Chen S, Geng S, Wu X, Zhong L, Schmidt CA, Przybylski GK: Reduced levels of recent thymic emigrants in acute myeloid leukemia patients. Cancer Immunol Immunother 2009, 58:1047-1055.
• [27]Hirsch B, Grunbaum M, Wagner F, Bi Y, Lucka L, Du MQ, Stein H, Durkop H: A novel A20 (TNFAIP3) antibody (Ber-A20) can be used to detect unmutated A20 by immunohistology. Histopathology 2012, 60:E19-E27.
• [28]Frenzel LP, Claus R, Plume N, Schwamb J, Konermann C, Pallasch CP, Claasen J, Brinker R, Wollnik B, Plass C, Wendtner CM: Sustained NF-kappaB activity in chronic lymphocytic leukemia is independent of genetic and epigenetic alterations in the TNFAIP3 (A20) locus. Int J Cancer 2011, 128:2495-2500.
• [29]Philipp C, Edelmann J, Buhler A, Winkler D, Stilgenbauer S, Kuppers R: Mutation analysis of the TNFAIP3 (A20) tumor suppressor gene in CLL. Int J Cancer 2011, 128:1747-1750.
• [30]Lawrence T: The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol 2009, 1:a001651.
• [31]Kato M, Sanada M, Kato I, Sato Y, Takita J, Takeuchi K, Niwa A, Chen Y, Nakazaki K, Nomoto J, Asakura Y, Muto S, Tamura A, Iio M, Akatsuka Y, Hayashi Y, Mori H, Igarashi T, Kurokawa M, Chiba S, Mori S, Ishikawa Y, Okamoto K, Tobinai K, Nakagama H, Nakahata T, Yoshino T, Kobayashi Y, Ogawa S: Frequent inactivation of A20 in B-cell lymphomas. Nature 2009, 459:712-716.
• [32]Malinverni C, Unterreiner A, Staal J, Demeyer A, Galaup M, Luyten M, Beyaert R, Bornancin F: Cleavage by MALT1 induces cytosolic release of A20. Biochem Biophys Res Commun 2010, 400:543-547.