Notch-mediated repression of miR-223 contributes to IGF1R regulation in T-ALL

Novel biological insights in T-cell acute lymphoblastic leukemia

“…This study was in line with other work that identified the miR-17-92 cluster as one of the most prominent oncogenic miRNA clusters able to induce overt T-cell leukemia in concert with activated NOTCH1 [67,68]. In addition, the role of miR-223 in oncogenic T-ALL signaling was also emphasized by others [69] and could be further validated through the identification of miR-223 as a direct target gene of the T-ALL oncogenes NOTCH1 [70] and TAL1, which contributes to T-ALL development by repression of the tumor suppressor gene FBXW7 [71]. Finally, another study identified miR-128-3p as a novel oncogenic miRNA in T-ALL that negatively regulates the expression of the tumor suppressor PHF6 [72] and cooperates with activated NOTCH1 signaling to accelerate T-ALL formation in vivo [72].…”

T-ALL and thymocytes: a message of noncoding RNAs

“…MiRNAs with the same target genes also showed a cooperative effect on cell viability. Three of these miRNAs ( miR - 19b , miR - 20a , and miR - 92 ) belong to the oncogenic miR - 17 ~ 92 cluster, whereas miR - 223 was subsequently shown to be activated by TAL1 [122, 123] and NOTCH1 [124], two important T-ALL oncogenes (discussed below), further supporting the original observations of this study.…”

“…MiR - 223 itself further negatively regulates FBXW7 , a known tumor suppressor gene in T-ALL. In contrast to this finding, γ-secretase inhibitor (GSI) treatment (which inhibits downstream NOTCH1 signaling) showed upregulation of miR-223 in GSI-resistant T-ALL cell lines [124]. These contradictory results could later be explained by the activation of C/EBPα after GSI treatment, which can activate miR - 223 as well [141].…”

Type I insulin-like growth factor receptor signaling in hematological malignancies

“…It was shown that Notch1 repressed the expression of microRNA-223, which, in turn, was able to decrease the expression IGF-IR protein. However, increased expression of microRNA-233 alone did not significantly hinder cell growth, alluding to the possibility that, in addition to the decrease in IGF-IR expression, modifications of other survival molecules are probably required to fully suppress T-ALL [167]. Another study showed that the forced expression of microRNA-99a and microRNA-100 inhibited the expression of IGF-IR and mTOR, as well as the downstream oncogenic proteins MCL1 and the FK506-binding protein 51 in T-ALL cell lines.…”