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      Independent oncogenic and therapeutic significance of phosphatase PRL-3 in FLT3-ITD–negative acute myeloid leukemia

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          Abstract

          BACKGROUND

          Internal tandem duplication of FMS-like tyrosine kinase (FLT3-ITD) is well known to be involved in acute myeloid leukemia (AML) progression, but FLT3-ITD–negative AML cases account for 70% to 80% of AML, and the mechanisms underlying their pathology remain unclear. This study identifies protein tyrosine phophatase PRL-3 as a key mediator of FLT3-ITD–negative AML.

          METHODS

          A total of 112 FLT3-ITD–negative AML patients were sampled between 2010 and 2013, and the occurrence of PRL-3 hyperexpression in FLT3-ITD–negative AML was evaluated by multivariate probit regression analysis. Overexpression or depletion of endogenous PRL-3 expression with the specific small interfering RNAs was performed to investigate the role of PRL-3 in AML progression. Xenograft models were also used to confirm the oncogenic role of PRL-3.

          RESULTS

          Compared to healthy donors, PRL-3 is upregulated more than 3-fold in 40.2% of FLT3-ITD–negative AML patients. PRL-3 expression level is adversely correlated to the overall survival of the AML patients, and the AML relapses accompany with re-upregulation of PRL-3. Mechanistically, aberrant PRL-3 expression promoted cell cycle progression and enhanced the antiapoptotic machinery of AML cells to drug cytotoxicity through downregulation of p21 and upregulation of Cyclin D1 and CDK2 and activation of STAT5 and AKT. Depletion of endogenous PRL-3 sensitizes AML cells to therapeutic drugs, concomitant with apoptosis by upregulation of cleaved PARP (poly ADP ribose polymerase) and apoptosis-related caspases. Xenograft assays further confirmed PRL-3’s oncogenic role in leukemogenesis.

          CONCLUSIONS

          Our results demonstrated that PRL-3 is a novel independent crucial player in both FLT3-ITD–positive and FLT3-ITD–negative AML and could be a potential therapeutic target. Cancer 2014;120:2130–2141. © 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

          FLT3-ITD–negative acute myeloid leukemia (AML) accounts for up to approximately 70% to 80% of all cases. This study demonstrates that PRL-3, an independent driver in FLT3-ITD–negative AML, is adversely correlated to patient survival. Mechanistically, PRL-3 can promote AML cell cycle progression and render antiapoptosis features to AML cells, suggesting it could be an independent factor for AML diagnosis and therapy.

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          Most cited references35

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          Acute myeloid leukaemia.

          Acute myeloid leukaemia (AML) is a heterogeneous clonal disorder of haemopoietic progenitor cells and the most common malignant myeloid disorder in adults. The median age at presentation for patients with AML is 70 years. In the past few years, research in molecular biology has been instrumental in deciphering the pathogenesis of the disease. Genetic defects are thought to be the most important factors in determining the response to chemotherapy and outcome. Whereas significant progress has been made in the treatment of younger adults, the prospects for elderly patients have remained dismal, with median survival times of only a few months. This difference is related to comorbidities associated with ageing and to disease biology. Current efforts in clinical research focus on the assessment of targeted therapies. Such new approaches will probably lead to an increase in the cure rate.
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            Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis.

            C Thiede (2002)
            Constitutive activation of the FLT3 receptor tyrosine kinase, either by internal tandem duplication (ITD) of the juxtamembrane region or by point mutations in the second tyrosine kinase domain (TKD), has been described in patients with acute myelogenous leukemia (AML). We analyzed the prevalence and the potential prognostic impact of FLT3 mutations in 979 AML patients. Results were correlated with cytogenetic data and the clinical response. FLT3-ITD mutations were found in 20.4% and FLT3-TKD mutations in 7.7% of the patients. Each mutation was associated with similar clinical characteristics and was more prevalent in patients with normal karyotype. Significantly more FLT3 aberrations were found in patients with FAB M5, and fewer were found in patients with FAB M2 and M6. Although less frequent in patients with cytogenetic aberrations, FLT3-ITDs were found in 13 of 42 patients with t(15;17) and in 9 of 10 patients with t(6;9). The prevalence of the ITD allele on the DNA level was heterogeneous, ranging from faint mutant bands in some patients to predominant mutant bands in others. Based on quantitative analysis, the mutant-wild-type (wt) ratio ranged from 0.03 to 32.56 (median, 0.78). Patients with a high mutant/wt ratio (ie, greater than 0.78) had significantly shorter overall and disease-free survival, whereas survival in patients with ratios below 0.78 did not differ from those without FLT3 aberrations. Multivariate analysis confirmed a high mutant/wt ratio to be a strong independent prognostic factor. Taken together, these data confirm that FLT mutations represent a common alteration in adult AML. Constitutive activation may be associated with monocytoid differentiation. A high mutant/wt ratio in ITD-positive patients appears to have a major impact on the prognostic relevance.
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              A phosphatase associated with metastasis of colorectal cancer.

              To gain insights into the molecular basis for metastasis, we compared the global gene expression profile of metastatic colorectal cancer with that of primary cancers, benign colorectal tumors, and normal colorectal epithelium. Among the genes identified, the PRL-3 protein tyrosine phosphatase gene was of particular interest. It was expressed at high levels in each of 18 cancer metastases studied but at lower levels in nonmetastatic tumors and normal colorectal epithelium. In 3 of 12 metastases examined, multiple copies of the PRL-3 gene were found within a small amplicon located at chromosome 8q24.3. These data suggest that the PRL-3 gene is important for colorectal cancer metastasis and provide a new therapeutic target for these intractable lesions.
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                Author and article information

                Journal
                Cancer
                Cancer
                cncr
                Cancer
                BlackWell Publishing Ltd (Oxford, UK )
                0008-543X
                1097-0142
                15 July 2014
                15 April 2014
                : 120
                : 14
                : 2130-2141
                Affiliations
                [1 ]Department of Hematology, the First Affiliated Hospital, Sun Yat-sen University Guangzhou, China
                [2 ]Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University Guangzhou, China
                [3 ]Translational Medicine Centre, the First Affiliated Hospital, Sun Yat-sen University Guangzhou, China
                [4 ]Center for Stem Cell Biology and Tissue Engineering, Sun Yat-sen University Guangzhou, China
                [5 ]Department of Hematology, Fujian Provincial Hospital, Fujian Medical University Fuzhou, China
                Author notes
                Corresponding authors: Xiuzhen Tong, MD, PhD, 58 Second Zhonshan Road, Guangzhou, CPZN 510080, People’s Republic of China, Telephone: (011) 86-20-87755766-8831; tongxz05@ 123456163.com , or Haihe Wang, PhD, 74 Second Zhonshan Road, Guangzhou, CPZN 510080, People’s Republic of China; Telephone: (011) 86-20-87335035; wanghaih@ 123456mail.sysu.edu.cn .
                Article
                10.1002/cncr.28668
                4231236
                24737397
                f67556ff-a11a-4b19-b565-a879b8ca4d04
                © 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society

                This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 03 October 2013
                : 21 November 2013
                : 08 January 2014
                Categories
                Original Articles

                Oncology & Radiotherapy
                acute myeloid leukemia,prl-3,flt3-itd–negative,apoptosis,drug resistance,cell proliferation

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