miR-9 is an essential oncogenic microRNA specifically overexpressed in
            <i>mixed lineage leukemia</i>
            –rearranged leukemia

Chen, Ping; Price, Colles; Li, Zejuan; Li, Yuanyuan; Cao, Deliang; Wiley, Anissa; He, Chunjiang; Gurbuxani, Sandeep; Kunjamma, Rejani B.; Huang, Hao; Jiang, Xi; Arnovitz, Stephen; Xu, Mengyi; Hong, Gia Ming; Elkahloun, Abdel G.; Neilly, Mary Beth; Wunderlich, Mark; Larson, Richard A.; Beau, Michelle M. Le; Mulloy, James C.; Liu, Paul P.; Rowley, Janet D.; Chen, Jianjun

doi:10.1073/pnas.1310144110

Cited by 98 publications

(82 citation statements)

References 41 publications

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“…48 For AML, miR-9 is the most specifically up-regulated microRNA in MLL-rearranged AML compared with other types of AML, as it is a target of MLL fusion proteins, and its expression directly correlates with disease progression. 49 In our study, miR-9 was an unfavorable prognostic factor. There are less studies about miR-203.…”

Section: Discussionsupporting

confidence: 50%

A 3-microRNA scoring system for prognostication in de novo acute myeloid leukemia patients

Chou

et al. 2014

Leukemia

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As a highly heterogeneous disease, acute myeloid leukemia (AML) needs fine risk stratification to get an optimal outcome of patients. MicroRNAs have florid biological functions and have critical roles in the pathogenesis and prognosis in AML. Expression levels of some single microRNAs are influential for prognosis, but a system integrating several together and considering the weight of each should be more powerful. We thus analyzed the clinical, genetic and microRNA profiling data of 138 de novo AML patients of our institute. By multivariate analysis, we identified that high expression of hsa-miR-9-5p and hsa-miR-155-5p were independent poor prognostic factors, whereas that of hsa-miR-203 had a trend to be a favorable factor. We constructed a scoring system from expression of these three microRNAs by considering the weight of each. The scores correlated with distinct clinical and biological features and outperformed single microRNA expression in prognostication. In both ours and another validation cohort, higher scores were associated with shorter overall survival, independent of other well-known prognostic factors. By analyzing the mRNA expression profiles, we sorted out several cancer-related pathways highly correlated with the microRNA prognostic signature. We conclude that this 3-microRNA scoring system is simple and powerful for risk stratification of de novo AML patients.

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Section: Discussionsupporting

confidence: 50%

A 3-microRNA scoring system for prognostication in de novo acute myeloid leukemia patients

Chou

et al. 2014

Leukemia

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“…Although microRNAs are globally down-regulated in AML [46], specific oncogenic miRNAs such as miR-9 [47] and miR-17 family members [48] are often found highly expressed in AML. Induction of RBM38 and DND1 during neutrophil differentiation may antagonize the activity of these oncomiRs by protecting mRNAs, including p21 CIP1 that are important for myeloid differentiation.…”

Section: Discussionmentioning

confidence: 99%

The RNA binding proteins RBM38 and DND1 are repressed in AML and have a novel function in APL differentiation

et al. 2016

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The RNA binding proteins RBM binding motif protein 38 (RBM38) and DEAD END 1 (DND1) selectively stabilize mRNAs by attenuating RNAse activity or protecting them from micro(mi)RNA-mediated cleavage. Furthermore, both proteins can efficiently stabilize the mRNA of the cell cycle inhibitor p21 CIP1 . Since acute myeloid leukemia (AML) differentiation requires cell cycle arrest and RBM38 as well as DND1 have antiproliferative functions, we hypothesized that decreased RBM38 and DND1 expression may contribute to the differentiation block seen in this disease. We first quantified RBM38 and DND1 mRNA expression in clinical AML patient samples and CD34 + progenitor cells and mature granulocytes from healthy donors. We found significantly lower RBM38 and DND1 mRNA levels in AML blasts and CD34 + progenitor cells as compared to mature neutrophils from healthy donors. Furthermore, the lowest expression of both RBM38 and DND1 mRNA correlated with t(8;21). In addition, neutrophil differentiation of CD34 + cells in vitro with G-CSF (granulocyte colony stimulating factor) resulted in a significant increase of RBM38 and DND1 mRNA levels. Similarly, neutrophil differentiation of NB4 acute promyelocytic leukemia (APL) cells was associated with a significant induction of RBM38 and DND1 expression. To address the function of RBM38 and DND1 in neutrophil differentiation, we generated two independent NB4_RBM38 as well as DND1 knockdown cell lines. Inhibition of both RBM38 and DND1 mRNA significantly attenuated NB4 differentiation and resulted in decreased p21 CIP1 mRNA expression. Our results clearly indicate that expression of the RNA binding proteins RBM38 and DND1 is repressed in primary AML patients, that neutrophil differentiation is dependent on increased expression of both proteins, and that these proteins have a critical role in regulating p21 CIP1 expression during APL differentiation. Highlights RBM38 and DND1 expression is attenuated in primary AML patients  Normal and leukemic neutrophil differentiation induces RBM38 and DND1 expression  New function for the RNA binding proteins RBM38 and DND1 in APL differentiation Keywords: RBM38, DND1, acute myeloid leukemia, acute promyelocytic leukemia, neutrophil differentiation

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“…In pancreatic beta cells, miR-9 has been proposed to negatively regulate insulin secretion [20]. MiR-9 acted as an oncogene in leukaemia [37], but as a tumour suppressor in hepatocellular carcinoma [38]. It is worth mentioning that we have not observed significant differences in body weight, plasma alanine transaminase (ALT) and aspartate transaminase (AST) levels and mortality of mice injected with miR-9 inhibitor or miR-9 mimic compared with mice injected with NC (data not shown).…”

Section: Discussionmentioning

confidence: 99%

A decrease in hepatic microRNA-9 expression impairs gluconeogenesis by targeting FOXO1 in obese mice

Yan

Chen

et al. 2016

Diabetologia

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Aim/hypothesis MicroRNA-9 (miR-9) is involved in the regulation of pancreatic beta cell function. However, its role in gluconeogenesis is still unclear. Our objective was to investigate the role of miR-9 in hepatic glucose production (HGP). Methods MiR-9 expression was measured in livers of high-fat diet (HFD) mice and ob/ob mice. The methylation status of the miR-9-3 promoter regions in hepatocytes was determined by the methylation-specific PCR procedure. The binding activity of DNA methyltransferase (DNMT)1, DNMT3a and DNMT3b on the miR-9-3 promoter was detected by chromatin immunoprecipitation (ChIP) and quantitative real-time PCR assays. HGP was evaluated in vitro and in vivo. Glucose tolerance, insulin tolerance and pyruvate tolerance tests were also performed. Results Reduced miR-9 expression and hypermethylation of the miR-9-3 promoter were observed in the livers of obese mice. Further study showed that the binding of DNMT1, but not of DNMT3a and DNMT3b, to the miR-9-3 promoter was increased in hepatocytes from ob/ob mice. Knockdown of DNMT1 alleviated the decrease in hepatic miR-9 expression in vivo and in vitro. Overexpression of hepatic miR-9 improved insulin sensitivity in obese mice and inhibited HGP. In addition, deletion of hepatic miR-9 led to an increase in random and fasting blood glucose levels in lean mice. Importantly, silenced forkhead box O1 (FOXO1) expression reversed the gluconeogenesis and glucose production in hepatocytes induced by miR-9 deletion. Conclusions/interpretation Our observations suggest that the decrease in miR-9 expression contributes to an inappropriately activated gluconeogenesis in obese mice.

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miR-9 is an essential oncogenic microRNA specifically overexpressed in mixed lineage leukemia –rearranged leukemia

Cited by 98 publications

References 41 publications

A 3-microRNA scoring system for prognostication in de novo acute myeloid leukemia patients

A 3-microRNA scoring system for prognostication in de novo acute myeloid leukemia patients

The RNA binding proteins RBM38 and DND1 are repressed in AML and have a novel function in APL differentiation

A decrease in hepatic microRNA-9 expression impairs gluconeogenesis by targeting FOXO1 in obese mice

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