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      TRIM proteins in blood cancers

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          Abstract

          Post-translational modification of proteins with ubiquitin plays a central role in regulating numerous cellular processes. E3 ligases determine the specificity of ubiquitination by mediating the transfer of ubiquitin to substrate proteins. The family of tripartite motif (TRIM) proteins make up one of the largest subfamilies of E3 ligases. Accumulating evidence suggests that dysregulation of TRIM proteins is associated with a variety of diseases. In this review we focus on the involvement of TRIM proteins in blood cancers.

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          Most cited references 38

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          A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1.

          To molecularly define high-risk disease, we performed microarray analysis on tumor cells from 532 newly diagnosed patients with multiple myeloma (MM) treated on 2 separate protocols. Using log-rank tests of expression quartiles, 70 genes, 30% mapping to chromosome 1 (P < .001), were linked to early disease-related death. Importantly, most up-regulated genes mapped to chromosome 1q, and down-regulated genes mapped to chromosome 1p. The ratio of mean expression levels of up-regulated to down-regulated genes defined a high-risk score present in 13% of patients with shorter durations of complete remission, event-free survival, and overall survival (training set: hazard ratio [HR], 5.16; P < .001; test cohort: HR, 4.75; P < .001). The high-risk score also was an independent predictor of outcome endpoints in multivariate analysis (P < .001) that included the International Staging System and high-risk translocations. In a comparison of paired baseline and relapse samples, the high-risk score frequency rose to 76% at relapse and predicted short postrelapse survival (P < .05). Multivariate discriminant analysis revealed that a 17-gene subset could predict outcome as well as the 70-gene model. Our data suggest that altered transcriptional regulation of genes mapping to chromosome 1 may contribute to disease progression, and that expression profiling can be used to identify high-risk disease and guide therapeutic interventions.
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            PML targeting eradicates quiescent leukaemia-initiating cells.

            The existence of a small population of 'cancer-initiating cells' responsible for tumour maintenance has been firmly demonstrated in leukaemia. This concept is currently being tested in solid tumours. Leukaemia-initiating cells, particularly those that are in a quiescent state, are thought to be resistant to chemotherapy and targeted therapies, resulting in disease relapse. Chronic myeloid leukaemia is a paradigmatic haematopoietic stem cell disease in which the leukaemia-initiating-cell pool is not eradicated by current therapy, leading to disease relapse on drug discontinuation. Here we define the critical role of the promyelocytic leukaemia protein (PML) tumour suppressor in haematopoietic stem cell maintenance, and present a new therapeutic approach for targeting quiescent leukaemia-initiating cells and possibly cancer-initiating cells by pharmacological inhibition of PML.
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              Loss of the tumor suppressor PML in human cancers of multiple histologic origins.

              The PML gene is fused to the RARalpha gene in the vast majority of acute promyelocytic leukemias (APL) and has been implicated in the control of key tumor-suppressive pathways. However, its role in the pathogenesis of human cancers other than APL is still unclear. We therefore assessed the status and expression of the PML gene in solid tumors of multiple histologic origins. We created tumor tissue microarrays (TTMs) with samples from patients with colon adenocarcinoma (n = 109), lung carcinoma (n = 19), prostate adenocarcinoma (n = 36), breast carcinoma (n = 38), central nervous system (CNS) tumors (n = 51), germ cell tumors (n = 60), thyroid carcinoma (n = 32), adrenal cortical carcinoma (n = 12), and non-Hodgkin's lymphoma (n = 251) and from normal tissue corresponding to each histotype and analyzed PML protein and mRNA expression by immunohistochemistry and in situ hybridization, respectively. Tumor cell lines (n = 64) of various histologic origins were analyzed for PML protein and mRNA expression by immunofluorescence and northern blotting, respectively. DNA from microdissected tumor samples and cell lines was analyzed for PML mutations and loss of heterozygosity (LOH). For some tumor types, the association between PML expression and tumor stage and grade was analyzed. Statistical tests were two-sided. All normal tissues expressed PML protein. PML protein expression was reduced or abolished in prostate adenocarcinomas (63% [95% confidence interval [CI] = 48% to 78%] and 28% [95% CI = 13% to 43%], respectively), colon adenocarcinomas (31% [95% CI = 22% to 40%] and 17% [95% CI = 10% to 24%]), breast carcinomas (21% [95% CI = 8% to 34%] and 31% [95% CI = 16% to 46%]), lung carcinomas (36% [95% CI = 15% to 57%] and 21% [95% = 3% to 39%]), lymphomas (14% [95% CI = 10% to 18%] and 69% [95% CI = 63% to 75%]), CNS tumors (24% [95% CI = 13% to 35%] and 49% [95% CI = 36% to 62%]), and germ cell tumors (36% [95% CI = 24% to 48%] and 48% [95% CI = 36% to 60%]) but not in thyroid or adrenal carcinomas. Loss of PML protein expression was associated with tumor progression in prostate cancer (the progression from prostatic intraepithelial neoplasia to invasive carcinoma was associated with complete PML loss; P<.001), breast cancer (complete PML loss was associated with lymph node metastasis; P =.01), and CNS tumors (complete PML loss was associated with high-grade tumors; P =.003). PML mRNA was expressed in all tumor and cell line samples. The PML gene was rarely mutated and was not subject to LOH. PML protein expression is frequently lost in human cancers of various histologic origins, and its loss associates with tumor grade and progression in some tumor histotypes.
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                Author and article information

                Contributors
                s.irvine@qub.ac.uk
                Journal
                J Cell Commun Signal
                J Cell Commun Signal
                Journal of Cell Communication and Signaling
                Springer Netherlands (Dordrecht )
                1873-9601
                1873-961X
                6 November 2017
                6 November 2017
                March 2018
                : 12
                : 1
                : 21-29
                Affiliations
                ISNI 0000 0004 0374 7521, GRID grid.4777.3, Centre for Cancer Research and Cell Biology, , Queen’s University Belfast, ; 97 Lisburn Road, Belfast, BT9 7BL UK
                Article
                423
                10.1007/s12079-017-0423-5
                5842186
                29110249
                © The Author(s) 2017

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100007903, Bloodwise;
                Award ID: 15043
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100000651, Leukaemia and Lymphoma Research;
                Categories
                Review
                Custom metadata
                © The International CCN Society 2018

                Cell biology

                multiple myeloma, trim proteins, ubiquitin, e3 ligase, leukaemia, lymphoma

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