Up-regulated A20 promotes proliferation, regulates cell cycle progression and induces chemotherapy resistance of acute lymphoblastic leukemia cells

Chen, Shuying; Xing, Haiyan; Li, Shouyun; Yu, Jing; Li, Huan; Liu, Shuang; Tian, Zheng; Tang, Kejing; Rao, Qing; Wang, Min; Wang, Jianxiang

doi:10.1016/j.leukres.2015.06.004

Cited by 17 publications

(21 citation statements)

References 31 publications

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“…A20 in PBMCs plays a key role in inflammatory disease, but A20 expression in PBMCs differs across diseases. Increased A20 expression has been demonstrated in the PBMCs of patients with acute lymphoblastic leukemia and acute-on-chronic hepatitis B liver failure (ACHBLF) (23,24), whereas decreased A20 levels have been observed in the PBMCs of patients with chronic inflammatory diseases such as type-2 diabetes and SLE (12,25). However, the protective role of A20 is widely accepted, and its diverse expression in different diseases does not seem to be relevant to this role.…”

Section: Discussionmentioning

confidence: 99%

A20 Ameliorates Intracerebral Hemorrhage–Induced Inflammatory Injury by Regulating TRAF6 Polyubiquitination

Meng

Zhao

Zhou

et al. 2017

The Journal of Immunology

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Reducing excessive inflammation is beneficial for the recovery from intracerebral hemorrhage (ICH). Here, the roles and mechanisms of A20 (TNFAIP3), an important endogenous anti-inflammatory factor, are examined in ICH. A20 expression in the PBMCs of ICH patients and an ICH mouse model was detected, and the correlation between A20 expression and neurologic deficits was analyzed. A20 expression was increased in PBMCs and was negatively related to the modified Rankin Scale score. A20 expression was also increased in mouse perihematomal tissues. A20−/− and A20-overexpressing mice were generated to further analyze A20 function. Compared with wild-type (WT) mice, A20−/− and A20-overexpressing mice showed significant increases and decreases, respectively, in hematoma volume, neurologic deficit score, mortality, neuronal degeneration, and proinflammatory factors. Moreover, WT-A20−/− parabiosis was established to explore the role of A20 in peripheral blood in ICH injury. ICH-induced damage, including brain edema, neurologic deficit score, proinflammatory factors, and neuronal apoptosis, was reduced in A20−/− parabionts compared with A20−/− mice. Finally, the interactions between TRAF6 and Ubc13 and UbcH5c were increased in A20−/− mice compared with WT mice; the opposite occurred in A20-overexpressing mice. Enhanced IκBα degradation and NF-κB activation were observed in A20−/− mice, but the results were reversed in A20-overexpressing mice. These results suggested that A20 is involved in regulating ICH-induced inflammatory injury in both the central and peripheral system and that A20 reduces ICH-induced inflammation by regulating TRAF6 polyubiquitination. Targeting A20 may thus be a promising therapeutic strategy for ICH.

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Section: Discussionmentioning

confidence: 99%

A20 Ameliorates Intracerebral Hemorrhage–Induced Inflammatory Injury by Regulating TRAF6 Polyubiquitination

Meng

Zhao

Zhou

et al. 2017

The Journal of Immunology

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“…Mounting evidence demonstrates that TNF alpha induced protein 3 (TNFAIP3) is a significant regulator of inflammation and immunity, which play important roles in the modulation of immune response to pathogens and the development of inflammatory and autoimmune disease [6][7][8]. Moreover, TNFAIP3 has been shown to be involved in several tumor biological features, including tumor radiosensitization [9], drug resistance [10], and cell proliferation [11]. However, few studies have investigated the role of TNFAIP3 in migration and invasion of NPC.…”

mentioning

confidence: 99%

TNFAIP3 inhibits migration and invasion in nasopharyngeal carcinoma by suppressing epithelial mesenchymal transition

Huang¹,

Yin²,

Wu³

et al. 2017

neo

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TNF alpha induced protein 3 (TNFAIP3), a member of zinc finger protein family, is a gene whose expression level is promptly induced by the tumor necrosis factor. In this study, the clinical significance of TNFAIP3 was analyzed based on available samples in The Cancer Genome Atlas database. TNFAIP3 downregulation was associated with distant metastasis and worse patient prognosis. TNFAIP3-overexpressing and TNFAIP3-knockdown NPC cell line models were established through plasmid-mediated overexpression and small interfering RNA (siRNA), respectively. Cell migration and invasion capacities were evaluated by wound-healing and transwell assays. Functional studies indicated that TNFAIP3 knockdown promoted migration and invasion, whereas TNFAIP3 overexpression alleviated these functions. Western blot analysis was used to examine protein changes from TNFAIP3 overexpression and knockdown, in which TNFAIP3 promoted the protein expression of E-cadherin and suppressed vimentin expression. Our data suggested that TNFAIP3 inhibited migration and invasion by suppressing epithelial mesenchymal transition in NPC.

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“…Genes for which the average enrichment of the two sgRNAs that scored in the screen was at least 2-fold are listed in Table 1. Among these genes are known regulators of apoptosis including A20 and MCL1, a BCL2 family protein 15,16 . Many of the sgRNAs that were increased after T cell killing were also enriched, albeit to a lesser extent, after 10 population doublings, suggesting that the targeted gene may affect both general cell fitness and sensitivity to CD3 bsAb (Supplemental Table 3).…”

Section: Resultsmentioning

confidence: 99%

Genome-scale CRISPR activation screen uncovers tumor-intrinsic modulators of CD3 bispecific antibody efficacy

Decker

Young

Pasnikowski

et al. 2019

Sci Rep

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Bispecific antibodies (bsAb) that bridge tumor cells and CD3-positive effector T cells are being developed against many tumor cell targets. While tumor cell factors other than target expression level appear to play a role in determining the efficacy of CD3 bsAb, the identity of such factors remains largely unknown. Using a co-culture system of primary human T cells and B lymphoma cell lines, we demonstrate a range of sensitivities to CD20xCD3 bsAb that is independent of CD20 surface expression. To identify genes that modulate tumor cell sensitivity to CD3 bsAb, we employed a genome-scale CRISPR activation screen in a CD20xCD3-sensitive human B lymphoma cell line. Among the most highly enriched sgRNAs were those targeting genes with predicted effects on cell-cell adhesion, including sialophorin (SPN). Increased expression of SPN impeded tumor cell clustering with T cells, thereby limiting CD3 bsAb-mediated tumor cell lysis. This inhibitory effect of SPN appeared to be dependent on sialylated core 2 O-glycosylation of the protein. While SPN is not endogenously expressed in the majority of B cell lymphomas, it is highly expressed in acute myeloid leukemia. CRISPR-mediated SPN knockout in AML cell lines facilitated T cell-tumor cell clustering and enhanced CD3 bsAb-mediated AML cell lysis. In sum, our data establish that the cell cross-linking mechanism of CD3 bsAb is susceptible to subversion by anti-adhesive molecules expressed on the tumor cell surface. Further evaluation of anti-adhesive pathways may provide novel biomarkers of clinical response and enable the development of effective combination regimens for this promising therapeutic class.

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Up-regulated A20 promotes proliferation, regulates cell cycle progression and induces chemotherapy resistance of acute lymphoblastic leukemia cells

Cited by 17 publications

References 31 publications

A20 Ameliorates Intracerebral Hemorrhage–Induced Inflammatory Injury by Regulating TRAF6 Polyubiquitination

A20 Ameliorates Intracerebral Hemorrhage–Induced Inflammatory Injury by Regulating TRAF6 Polyubiquitination

TNFAIP3 inhibits migration and invasion in nasopharyngeal carcinoma by suppressing epithelial mesenchymal transition

Genome-scale CRISPR activation screen uncovers tumor-intrinsic modulators of CD3 bispecific antibody efficacy

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