CBFA2T3‐GLIS2‐positive acute myeloid leukaemia. A peculiar paediatric entity

Masetti, Riccardo; Bertuccio, Salvatore Nicola; Pession, Andrea; Locatelli, Franco

doi:10.1111/bjh.15725

Cited by 48 publications

(50 citation statements)

References 46 publications

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“…ETO2 or MTG16) gene on the long arm of chromosome 16, encoding a transcriptional co-repressor, is targeted by two recurrent AML-associated chromosomal rearrangements, the t(16;21)(q24;q22) and the cytogenetically silent inv(16) (p13q24) leading to expression of RUNX1–CBFA2T3 and CBFA2T3–GLIS2 fusions, respectively. Whereas, the first is more prevalent in therapy-related adult AML and rarely found in pediatric patients, the second appears to be an exclusive pediatric lesion (19, 20). NGS strategies allowed the identification of the CBFA2T3–GLIS2 fusion from tumor cells of pediatric patients with de novo acute megakaryoblastic leukemia (non-DS AMKL) (21, 22).…”

Section: Genomic Landscape Of Pediatric Amlmentioning

confidence: 99%

Pediatric Acute Myeloid Leukemia (AML): From Genes to Models Toward Targeted Therapeutic Intervention

Mercher

Schwaller

2019

Front. Pediatr.

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This review aims to provide an overview of the current knowledge of the genetic lesions driving pediatric acute myeloid leukemia (AML), emerging biological concepts, and strategies for therapeutic intervention. Hereby, we focus on lesions that preferentially or exclusively occur in pediatric patients and molecular markers of aggressive disease with often poor outcome including fusion oncogenes that involve epigenetic regulators like KMT2A, NUP98, or CBFA2T3, respectively. Functional studies were able to demonstrate cooperation with signaling mutations leading to constitutive activation of FLT3 or the RAS signal transduction pathways. We discuss the issues faced to faithfully model pediatric acute leukemia in mice. Emerging experimental evidence suggests that the disease phenotype is dependent on the appropriate expression and activity of the driver fusion oncogenes during a particular window of opportunity during fetal development. We also highlight biochemical studies that deciphered some molecular mechanisms of malignant transformation by KMT2A, NUP98, and CBFA2T3 fusions, which, in some instances, allowed the development of small molecules with potent anti-leukemic activities in preclinical models (e.g., inhibitors of the KMT2A–MENIN interaction). Finally, we discuss other potential therapeutic strategies that not only target driver fusion-controlled signals but also interfere with the transformed cell state either by exploiting the primed apoptosis or vulnerable metabolic states or by increasing tumor cell recognition and elimination by the immune system.

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Section: Genomic Landscape Of Pediatric Amlmentioning

confidence: 99%

Pediatric Acute Myeloid Leukemia (AML): From Genes to Models Toward Targeted Therapeutic Intervention

Mercher

Schwaller

2019

Front. Pediatr.

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“…By the way, GLIS2, the other intersected target gene of miR-138-2-3p, is a member of GLI-similar zinc finger protein family and is closely linked with acute myeloid leukaemia, has been also noted to correlated with tumor progression [49,50]. We would like to investigate if Fig.…”

Section: Discussionmentioning

confidence: 99%

Long non-coding RNA NCK1-AS1 promotes the tumorigenesis of glioma through sponging microRNA-138-2-3p and activating the TRIM24/Wnt/β-catenin axis

Huang

et al. 2020

J Exp Clin Cancer Res

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Background: Glioma is a common brain malignancy with high mortality. The competing endogenous RNA (ceRNA) networks may play key roles in cancer progression. This study was conducted to probe the role of long noncoding RNA (lncRNA) NCK1-AS1 in glioma progression and the involved mechanisms.Methods: Microarray analyses were performed to explore the lncRNAs/miRNAs/genes with differential expression in glioma. NCK1-AS1 levels in glioma tissues and normal brain tissues, and in glioma cell lines and normal human glial cells were identified. The interactions among NCK1-AS1, miR-138-2-3p and TRIM24 were validated through luciferase reporter, RNA immunoprecipitation and RNA pull-down assays. Gain-and loss-of functions of NCK1-AS1, miR-138-2-3p and TRIM24 were performed to identify their roles in the behaviors of glioma cells. The activity of the Wnt/β-catenin pathway was measured. In vivo experiments were performed as well.Results: High expression of NCK1-AS1 was found in glioma tissues and cells, especially in U251 cells. Online predictions and the integrated experiments identified that NCK1-AS1 elevated the TRIM24 expression through sponging miR-138-2-3p, and further activated the Wnt/β-catenin pathway. Artificial silencing of NCK1-AS1 or upregulation of miR-138-2-3p led to inhibited proliferation, invasion and migration but promoted cell apoptosis of U251 cells, while up-regulation of TRIM24 reversed these changes, and it activated the Wnt/β-catenin pathway. The in vitro results were reproduced in in vivo experiments.Conclusions: Our study suggested that NCK1-AS1 might elevate TRIM24 expression and further activate the Wnt/βcatenin pathway via acting as a ceRNA for miR-138-2-3p. Silencing of NCK1-AS1 might inhibit the progression of glioma.

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“…The mechanisms of the association between GLIS2 and radiotherapy are still not clear. According to the report published by Masetti et al [31], CBFA2T3-GLIS2 is the most frequent chimeric oncogene identified in non-Down's syndrome acute megakaryocytic leukemia (non-DS-AMKL). It regulated molecules involved in the Hedgehog pathway and Wingless/Integrated (WNT)/ β -catenin pathways, such as GATA3, HHIP and β -catenin.…”

Section: Discussionmentioning

confidence: 99%

Low Expression of GLIS2 Gene Might Associate with Radiosensitivity of Gastric Cancer

Sun

et al. 2019

Journal of Oncology

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Human gene GLIS family zinc finger 2 (GLIS2) is a member of GLI-similar zinc finger protein family. Previous studies indicated GLIS2 gene involved in tumorigenesis mechanisms. However, the association between GLIS2 expression and radiosensitivity of gastric cancer has not been well understood. In this study, we used the gastric cancer database in TCGA, and significant association was observed between the low expression of GLIS2 and radiosensitivity of patients with gastric cancer. The adjusted HR values for radiotherapy were 0.162(0.035-0.756) and 0.089(0.014-0.564), with p values 0.021 and 0.010, respectively, in training and testing data, for these patients with low expression of GLIS2, while for patients with high expression of GLIS2, there was no significant survival difference between radiotherapy and nonradiotherapy groups. The adjusted HR were 0.676(0.288-1.586) and 0.508(0.178-1.450), with p values 0.368 and 0.206 in training and testing data, respectively. Further study showed that, for low expression patients, radiotherapy did not significantly increase new tumor event rate and disease progression rate, which partially supported our assumption. These results suggested that low expression of GLIS2 might significantly associate with the radiosensitivity of patients with gastric cancer. The GLIS2 gene might be a potential effective molecular marker of gastric cancer for precise radiotherapy.

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CBFA2T3‐GLIS2‐positive acute myeloid leukaemia. A peculiar paediatric entity

Cited by 48 publications

References 46 publications

Pediatric Acute Myeloid Leukemia (AML): From Genes to Models Toward Targeted Therapeutic Intervention

Pediatric Acute Myeloid Leukemia (AML): From Genes to Models Toward Targeted Therapeutic Intervention

Long non-coding RNA NCK1-AS1 promotes the tumorigenesis of glioma through sponging microRNA-138-2-3p and activating the TRIM24/Wnt/β-catenin axis

Low Expression of GLIS2 Gene Might Associate with Radiosensitivity of Gastric Cancer

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