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Overexpression of MALT1-A20-NF-?B in adult B-cell acute lymphoblastic leukemia.

ABSTRACT: BACKGROUND:A20 is a dual inhibitor of NF-?B activation and apoptosis in the tumor necrosis factor receptor 1 signaling pathway, and both are related to tumorigenesis. A20 is frequently inactivated by deletions and/or mutations in several B and T cell lymphoma subtypes; however, knowledge of the role of A20 in B-cell acute lymphoblastic leukemia (B-ALL) remains limited. In this study, we characterized the A20 gene expression pattern, the expression level of its upstream regulating factor MALT1, and its downstream target NF-?B in adult B-ALL. METHODS:The expression level of MALT1, A20 and NF-?B1 was detected in peripheral blood mononuclear cells (PBMCs) from 20 patients with adult B-ALL (including 12 de novo B-ALL and 8 refractory/relapse B-ALL cases), and nine patients with B-ALL in complete remission (CR) using real-time PCR. Sixteen healthy individuals served as controls. RESULTS:Significant A20 overexpression was found in the B-ALL (median: 13.489) compared with B-ALL CR (median: 3.755) (P = 0.003) patients and healthy individuals (median: 8.748) (P = 0.002), while there was no significant difference in A20 expression between B-ALL CR patients and healthy individuals (P = 0.107). Interestingly, the A20 expression level in the B-ALL samples was relatively different with approximately 50% of the B-ALL cases showing a relatively high A20 expression level, while the remaining 50% cases demonstrated slight upregulation or a similar expression level as the healthy controls. However, there was no significant difference in the A20 expression level between de novo B-ALL (median 12.252) and refractory/relapse B-ALL patients (median 21.342) (P = 0.616). Similarly, a significantly higher expression level of NF-?B1 was found in the B-ALL (median 1.062) patients compared with healthy individuals (median 0.335) (P < 0.0001), while the NF-?B1 expression level was downregulated in the B-ALL CR group (median 0.339), which was significantly lower than that in those with B-ALL (P = 0.001). Moreover, the MALT1 expression level in B-ALL was upregulated (median 1.938) and significantly higher than that in healthy individuals (median 0.677) (P = 0.002) and B-ALL CR patients (median 0.153) (P = 0.008). The correlation of the expression levels of all three genes was lost in B-ALL. CONCLUSIONS:We found that MALT1-A20-NF-?B is overexpressed in adult B-ALL, which may be related to the pathogenesis of B-ALL, and this pathway may be considered a potentially attractive target for the development of B-ALL therapeutics.

SUBMITTER: Xu Y

PROVIDER: S-EPMC4514975 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Overexpression of MALT1-A20-NF-κB in adult B-cell acute lymphoblastic leukemia.

Xu Yi Y Hu Junyan J Wang Xu X Xuan Li L Lai Jing J Xu Ling L Chen Shaohua S Yang Lijian L Luo Gengxin G Zhu Kanger K Wu Xiuli X Li Yangqiu Y

Cancer cell international 20150725

<h4>Background</h4>A20 is a dual inhibitor of NF-κB activation and apoptosis in the tumor necrosis factor receptor 1 signaling pathway, and both are related to tumorigenesis. A20 is frequently inactivated by deletions and/or mutations in several B and T cell lymphoma subtypes; however, knowledge of the role of A20 in B-cell acute lymphoblastic leukemia (B-ALL) remains limited. In this study, we characterized the A20 gene expression pattern, the expression level of its upstream regulating factor ...[more]

PMID: 26213496

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Project description:UnlabelledGene expression studies have consistently identified a HOXA-overexpressing cluster of T-cell acute lymphoblastic leukemias, but it is unclear whether these constitute a homogeneous clinical entity, and the biological consequences of HOXA overexpression have not been systematically examined. We characterized the biology and outcome of 55 HOXA-positive cases among 209 patients with adult T-cell acute lymphoblastic leukemia uniformly treated during the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003 and -2005 studies. HOXA-positive patients had markedly higher rates of an early thymic precursor-like immunophenotype (40.8% versus 14.5%, P=0.0004), chemoresistance (59.3% versus 40.8%, P=0.026) and positivity for minimal residual disease (48.5% versus 23.5%, P=0.01) than the HOXA-negative group. These differences were due to particularly high frequencies of chemoresistant early thymic precursor-like acute lymphoblastic leukemia in HOXA-positive cases harboring fusion oncoproteins that transactivate HOXA Strikingly, the presence of an early thymic precursor-like immunophenotype was associated with marked outcome differences within the HOXA-positive group (5-year overall survival 31.2% in HOXA-positive early thymic precursor versus 66.7% in HOXA-positive non-early thymic precursor, P=0.03), but not in HOXA-negative cases (5-year overall survival 74.2% in HOXA-negative early thymic precursor versus 57.2% in HOXA-negative non-early thymic precursor, P=0.44). Multivariate analysis further revealed that HOXA positivity independently affected event-free survival (P=0.053) and relapse risk (P=0.039) of chemoresistant T-cell acute lymphoblastic leukemia. These results show that the underlying mechanism of HOXA deregulation dictates the clinico-biological phenotype, and that the negative prognosis of early thymic precursor acute lymphoblastic leukemia is exclusive to HOXA-positive patients, suggesting that early treatment intensification is currently suboptimal for therapeutic rescue of HOXA-positive chemoresistant adult early thymic precursor acute lymphoblastic leukemia.Trial registrationThe GRAALL-2003 and -2005 studies were registered at http://www.clinicaltrials.gov as #NCT00222027 and #NCT00327678, respectively.

Dataset Information

Overexpression of MALT1-A20-NF-?B in adult B-cell acute lymphoblastic leukemia.

Publications

Overexpression of MALT1-A20-NF-κB in adult B-cell acute lymphoblastic leukemia.

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