Targeting miR‐193a‐AML1‐ETO‐β‐catenin axis by melatonin suppresses the self‐renewal of leukaemia stem cells in leukaemia with t (8;21) translocation

Zhou, Bin; Ye, Haige; Xing, Chongyun; Liang, Bin; Li, Haiying; Chen, Linling; Huang, Xingzhou; Wu, Yanfei; Gao, Shenmeng

doi:10.1111/jcmm.14399

Cited by 8 publications

(3 citation statements)

References 54 publications

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“…The ribosome is a complex molecular machine responsible for protein synthesis in every living cell; additionally, ribosome biogenesis is the machinery that performs protein synthesis. Here we found that cabozantinib inhibited phosphorylation of p70S6K and 4E-BP1, and reduced the protein synthesis of AML1-ETO without increasing its degradation, unlike several anticancer agents that facilitate proteasomal degradation of AML1-ETO oncoprotein [ 38 – 40 ]. In addition, we clearly excluded the possibility that AML1-ETO dysregulation could be attributed to the cabozantinib-mediated acceleration of the turnover rate by using protein synthesis inhibitor CHX.…”

Section: Discussionmentioning

confidence: 97%

Repurposing cabozantinib with therapeutic potential in KIT-driven t(8;21) acute myeloid leukaemias

et al. 2021

Cancer Gene Ther

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Cabozantinib is an orally available, multi-target tyrosine kinase inhibitor approved for the treatment of several solid tumours and known to inhibit KIT tyrosine kinase. In acute myeloid leukaemia (AML), aberrant KIT tyrosine kinase often coexists with t(8;21) to drive leukaemogenesis. Here we evaluated the potential therapeutic effect of cabozantinib on a selected AML subtype characterised by t(8;21) coupled with KIT mutation. Cabozantinib exerted substantial cytotoxicity in Kasumi-1 cells with an IC50 of 88.06 ± 4.32 nM, which was well within clinically achievable plasma levels. The suppression of KIT phosphorylation and its downstream signals, including AKT/mTOR, STAT3, and ERK1/2, was elicited by cabozantinib treatment and associated with subsequent alterations of cell cycle- and apoptosis-related molecules. Cabozantinib also disrupted the synthesis of an AML1-ETO fusion protein in a dose- and time-dependent manner. In a mouse xenograft model, cabozantinib suppressed tumourigenesis at 10 mg/kg and significantly prolonged survival of the mice. Further RNA-sequencing analysis revealed that mTOR-mediated signalling pathways were substantially inactivated by cabozantinib treatment, causing the downregulation of ribosome biogenesis and glycolysis, along with myeloid leukocyte activation. We suggest that cabozantinib may be effective in the treatment of AML with t(8;21) and KIT mutation. Relevant clinical trials are warranted.

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Section: Discussionmentioning

confidence: 97%

Repurposing cabozantinib with therapeutic potential in KIT-driven t(8;21) acute myeloid leukaemias

et al. 2021

Cancer Gene Ther

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“…MicroRNAs, which are natural inhibitors of multiple genes, are attractive therapeutic molecules provided they are exclusively tumor-suppressive or oncogenic. MiR-193a has been reported to be tumor-suppressive in multiple cancers by downregulating several oncogenic targets [45][46][47][48]. Hence it is potentially a good therapeutic small molecule.…”

Section: Discussionmentioning

confidence: 99%

Restoration of miR-193a expression is tumor-suppressive in MYC amplified Group 3 medulloblastoma

Bharambe

Joshi

Yogi

et al. 2020

acta neuropathol commun

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Medulloblastoma, a highly malignant pediatric brain tumor, consists of four molecular subgroups, namely WNT, SHH, Group 3, and Group 4. The expression of miR-193a, a WNT subgroup-specific microRNA, was found to be induced by MYC, an oncogenic target of the canonical WNT signaling. MiR-193a is not expressed in Group 3 medulloblastomas, despite MYC expression, as a result of promoter hypermethylation. Restoration of miR-193a expression in the MYC amplified Group 3 medulloblastoma cells resulted in inhibition of growth, tumorigenicity, and an increase in radiation sensitivity. MAX, STMN1, and DCAF7 were identified as novel targets of miR-193a. MiR-193a mediated downregulation of MAX could suppress MYC activity since it is an obligate hetero-dimerization partner of MYC. MYC induced expression of miR-193a, therefore, seems to act as a feedback inhibitor of MYC signaling. The expression of miR-193a resulted in widespread repression of gene expression that included not only several cell cycle regulators, WNT, NOTCH signaling genes, and those encoding DNA replication machinery, but also several chromatin modifiers like SWI/SNF family genes and histone-encoding genes. MiR-193a expression brought about a reduction in the global levels of H3K4me3, H3K27ac, the histone marks of active chromatin, and an increase in the levels of H3K27me3, a repressive chromatin mark. In cancer cells having high MYC expression, MYC brings about transcriptional amplification of all active genes apart from the induction of its target genes. MiR-193a, on the other hand, brought about global repression of gene expression. Therefore, miR-193a has therapeutic potential in the treatment of not only Group 3 medulloblastomas but possibly other MYC overexpressing aggressive cancers as well.

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“…In these cells, melatonin was shown to downregulate Sox9, i.e., a factor that induces various osteoblast-typical genes, and to inhibit proliferation [241]. In leukemia stem cells, inhibition of proliferating self-renewal by melatonin was reported to be mediated by upregulation of miR-193a, which targets AML1-ETO, an oncogenic fusion gene formed by translocation, whose protein is known to increase β-catenin levels [242].…”

Section: Some Aspects Concerning Cancer Stem Cellsmentioning

confidence: 99%

Melatonin and the Programming of Stem Cells

Hardeland

2022

IJMS

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Melatonin interacts with various types of stem cells, in multiple ways that comprise stimulation of proliferation, maintenance of stemness and self-renewal, protection of survival, and programming toward functionally different cell lineages. These various properties are frequently intertwined but may not be always jointly present. Melatonin typically stimulates proliferation and transition to the mature cell type. For all sufficiently studied stem or progenitor cells, melatonin’s signaling pathways leading to expression of respective morphogenetic factors are discussed. The focus of this article will be laid on the aspect of programming, particularly in pluripotent cells. This is especially but not exclusively the case in neural stem cells (NSCs) and mesenchymal stem cells (MSCs). Concerning developmental bifurcations, decisions are not exclusively made by melatonin alone. In MSCs, melatonin promotes adipogenesis in a Wnt (Wingless-Integration-1)-independent mode, but chondrogenesis and osteogenesis Wnt-dependently. Melatonin upregulates Wnt, but not in the adipogenic lineage. This decision seems to depend on microenvironment and epigenetic memory. The decision for chondrogenesis instead of osteogenesis, both being Wnt-dependent, seems to involve fibroblast growth factor receptor 3. Stem cell-specific differences in melatonin and Wnt receptors, and contributions of transcription factors and noncoding RNAs are outlined, as well as possibilities and the medical importance of re-programming for transdifferentiation.

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Targeting miR‐193a‐AML1‐ETO‐β‐catenin axis by melatonin suppresses the self‐renewal of leukaemia stem cells in leukaemia with t (8;21) translocation

Cited by 8 publications

References 54 publications

Repurposing cabozantinib with therapeutic potential in KIT-driven t(8;21) acute myeloid leukaemias

Repurposing cabozantinib with therapeutic potential in KIT-driven t(8;21) acute myeloid leukaemias

Restoration of miR-193a expression is tumor-suppressive in MYC amplified Group 3 medulloblastoma

Melatonin and the Programming of Stem Cells

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