Distinct associations of NEDD4L expression with genetic abnormalities and prognosis in acute myeloid leukemia.

BACKGROUND: There is mounting evidence that demonstrated the association of aberrant NEDD4L expression with diverse human cancers. However, the expression pattern and clinical implication of NEDD4L in acute myeloid leukemia (AML) remains poorly defined. METHODS: We systemically determined NEDD4L expression with its clinical significance in AML by both public data and our research cohort. Moreover, biological functions of NEDD4L in leukemogenesis were further tested by in vitro experiments. RESULTS: By the public data, we identified that low NEDD4L expression was correlated with AML among diverse human cancers. Expression of NEDD4L was remarkably decreased in AML compared with controls, and was confirmed by our research cohort. Clinically, low expression of NEDD4L was correlated with greatly lower age, higher white blood cells, and higher bone marrow/peripheral blood blasts. Moreover, NEDD4L underexpression was positively correlated with normal karyotype, FLT3 and NPM1 mutations, but negatively associated with complex karyotype and TP53 mutations. Importantly, the association between NEDD4L expression and survival was also discovered in cytogenetically normal AML patients. Finally, a number of 1024 RNAs and 91 microRNAs were identified to be linked to NEDD4L expression in AML. Among the negatively correlated microRNAs, miR-10a was also discovered as a microRNA that may directly target NEDD4L. Further functional studies revealed that NEDD4L exhibited anti-proliferative and pro-apoptotic effects in leukemic cell line K562. CONCLUSIONS: Our findings indicated that NEDD4L underexpression, as a frequent event in AML, was associated with genetic abnormalities and prognosis in AML. Moreover, NEDD4L expression may be involved in leukemogenesis with potential therapeutic target value.

Expression and prognosis analysis of DNMT family in acute myeloid leukemia.

DNA methyltransferases (DNMTs) by regulating DNA methylation play crucial roles in the progression of hematologic malignancies, especially for acute myeloid leukemia (AML). Accumulating investigations have identified the high incidence of DNMT3A mutation in AML, and it is correlated with poor prognosis. Although a few studies have shown the expression of DNMTs and their clinical significance in AML, the results remain to be discussed. Herein, we systemically analyzed the DNMTs expression and their relationship with clinic-pathological features and prognosis in AML patients. DNMTs expression especially for DNMT3A/3B was closely associated with AML among various human cancers. DNMT3A expression was increased in AML patients, whereas DNMT3B expression was decreased. Significant associations between DNMT3A/B expression and clinic-pathological features/gene mutations were observed. Kaplan-Meier analysis showed that DNMT3A expression was associated with better overall survival (OS) and leukemia-free survival (LFS) among whole-cohort AML, and independently affected OS determined by Cox repression multivariate analysis. Notably, patients that received hematopoietic stem cell transplantation (HSCT) showed significantly better OS and LFS in DNMT3A lower-expressed groups, whereas patients in DNMT3A higher-expressed groups did not. By bioinformatics analysis, DNMT3A expression was found to be positively correlated with several leukemia-associated genes/microRNAs, and DNMT3A was identified as direct targets of miR-429 and miR-29b in AML. Collectively, our study demonstrated that DNMT3A/3B showed significant expression differences in AML. DNMT3A expression acted as a potential prognostic biomarker and may guide treatment choice between chemotherapy and HSCT in AML.

Dysregulation of miR-200s clusters as potential prognostic biomarkers in acute myeloid leukemia.

BACKGROUND: Increasing studies showed that miR-200 family (miR-200s) clusters are aberrantly expressed in multiple human cancers, and miR-200s clusters function as tumor suppressor genes by affecting cell proliferation, self-renewal, differentiation, division and apoptosis. Herein, we aimed to investigate the expression and clinical implication of miR-200s clusters in acute myeloid leukemia (AML). METHODS: RT-qPCR was performed to detect expression of miR-200s clusters in 19 healthy donors, 98 newly diagnosed AML patients, and 35 AML patients achieved complete remission (CR). RESULTS: Expression of miR-200a/200b/429 cluster but not miR-200c/141 cluster was decreased in newly diagnosed AML patients as compared to healthy donors and AML patients achieved CR. Although no significant differences were observed between miR-200s clusters and most of the features, low expression of miR-200s clusters seems to be associated with higher white blood cells especially for miR-200a/200b. Of the five members of miR-200s clusters, low expression of miR-200b/429/200c was found to be associated with lower CR rate. Logistic regression analysis further revealed that low expression of miR-429 acted as an independent risk factor for CR in AML. Based on Kaplan-Meier analysis, low expression of miR-200b/429/200c was associated with shorter OS, whereas miR-200a/141 had a trend. Moreover, multivariate analysis of Cox regression models confirmed the independently prognostic value of miR-200b expression for OS in AML. CONCLUSIONS: Expression of miR-200a/200b/429 cluster was frequently down-regulated in AML, and low expression of miR-429 as an independent risk factor for CR, whereas low expression of miR-200b as an independent prognostic biomarker for OS.