High CIP2A levels correlate with an antiapoptotic phenotype that can be overcome by targeting BCL-XL in chronic myeloid leukemia

Lucas, Claire; Milani, Mateus; Butterworth, Michael; Carmell, Natasha; Scott, Laura J.; Clark, Richard E.; Cohen, Gerald M.; Varadarajan, Shankar

doi:10.1038/leu.2016.42

Cited by 26 publications

(24 citation statements)

References 45 publications

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“…The study of BCL2L1 expression by molecular changes strongly supports its involvement in ABT‐263/PP242‐induced CML‐BC progenitor cells. Apoptosis may also be a novel therapeutic target in CML (Lucas et al, ). CML can be treated using a combination of these 11 genes.…”

Section: Discussionmentioning

confidence: 99%

Identification of key candidate targets and pathways for the targeted treatment of leukemia stem cells of chronic myelogenous leukemia using bioinformatics analysis

Liu

Zhuang

et al. 2019

Molec Gen & Gen Med

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Background Chronic myelogenous leukemia (CML) is a myeloproliferative neoplasm that arises from the acquisition of constitutively active BCR‐ABL tyrosine kinase in hematopoietic stem cells. The persistence of bone marrow leukemia stem cells (LSCs) is the main cause of TKI resistance and CML relapse. Therefore, finding a key target or pathway to selectively target LSCs is of great significance for the thorough treatment of CML. Methods In this study, we aimed to identify key microRNAs, microRNA targets and pathways for the treatment of CML LSCs by integrating analyses of three microarray data profiles. We identified 51 differentially expressed microRNAs through integrated analysis of GSE90773 and performed functional gene predictions for microRNAs. Then, GSE11889 and GSE11675 were integrated to obtain differentially expressed genes (DEGs), and the overlapping DEGs were used as models to identify predictive functional genes. Finally, we identified 116 predictive functional genes. Clustering and significant enrichment analysis of 116 genes was based on function and signaling pathways. Subsequently, a protein interaction network was constructed, and module analysis and topology analysis were performed on the network. Results A total of 11 key candidate targets and 33 corresponding microRNAs were identified. The key pathways were mainly concentrated on the PI3K/AKT, Ras, JAK/STAT, FoxO and Notch signaling pathways. We also found that LSCs negatively regulated endogenous and exogenous apoptotic pathways to escape from apoptosis. Conclusion We identified key candidate targets and pathways for CML LSCs through bioinformatics methods, which improves our understanding of the molecular mechanisms of CML LSCs. These candidate genes and pathways may be therapeutic targets for CML LSCs.

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Section: Discussionmentioning

confidence: 99%

Identification of key candidate targets and pathways for the targeted treatment of leukemia stem cells of chronic myelogenous leukemia using bioinformatics analysis

Liu

Zhuang

et al. 2019

Molec Gen & Gen Med

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“…Overexpression of Bcl-xL can inhibit disruption of the DeltaPsim (inner mitochondrial membrane potential) and reduce generation of ROS and MMP (21). The growth-promoting activity of Bcl-xL has been explored in a series of overexpression and gene knockout studies (6,22). …”

Section: Discussionmentioning

confidence: 99%

“…The transcription factor, STAT1 exerts its pro-apoptotic function by inducing the expression of caspases or by inhibiting growth-promoting NF-κB signals (5). Bcl-xL is a member of the anti-apoptotic Bcl-2 family protein, key regulators of the mitochondrial apoptosis pathway (6). …”

Section: Introductionmentioning

confidence: 99%

The effect of miR-146a on STAT1 expression and apoptosis in acute lymphoblastic leukemia Jurkat cells

Wang¹,

Guo²,

Suo³

et al. 2016

Oncology Letters

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The effect of miR-146a-dependent regulation of STAT1 on apoptosis in acute lymphoblastic leukemia (ALL) Jurkat cells was investigated. The miR-146a mimic and miR-146a inhibitor vectors were constructed in vitro, and experimental grouping was as follows: Control group (untreated Jurkat cells), empty vector group (Jurkat cells transfected with empty vector), agonist group (Jurkat cells transfected with miR-146a mimic) and the inhibitor group (Jurkat cells transfected with miR-146a inhibitor). Western blot analysis was used to observe the expression, respectively, of STAT1, p-STAT1 and Bcl-xL, and flow cytometry was used to test apoptosis in Jurkat cells. STAT1 and p-STAT1 expression in the agonist group was higher than that in the control and empty vector groups, but lower in the inhibitor group, and differences were statistically significant (P<0.05). The rate of apoptosis in the agonist group was significantly higher than that of the control group and blank vector group, and it was significantly lower in the inhibitor group (P<0.05). As a tumor suppressor, miR-146a can regulate expression of apoptosis-promoting factor STAT1, and anti-apoptosis factor Bcl-xL, and is able to promote apoptosis of ALL Jurkat cells.

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“…Additionally, CIP2A has been reported to be a translocation partner with the mixed-lineage leukemia (MLL) gene [117]. In CML, CIP2A is also biologically and clinically important [96,118], as high levels correlate not only with increased levels of MYC, but with upregulation of the antiapoptotic protein BCL-XL [97], another important target of PP2A [119]. Additionally, CIP2A mRNA and protein content is regulated by MYC, creating a positive feedback loop between the two oncogenes in cancer [95].…”

Section: Arpp19mentioning

confidence: 99%

The Role of MYC and PP2A in the Initiation and Progression of Myeloid Leukemias

Pippa

Odero

2020

Cells

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The MYC transcription factor is one of the best characterized PP2A substrates. Deregulation of the MYC oncogene, along with inactivation of PP2A, are two frequent events in cancer. Both proteins are essential regulators of cell proliferation, apoptosis, and differentiation, and they, directly and indirectly, regulate each other’s activity. Studies in cancer suggest that targeting the MYC/PP2A network is an achievable strategy for the clinic. Here, we focus on and discuss the role of MYC and PP2A in myeloid leukemias.

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High CIP2A levels correlate with an antiapoptotic phenotype that can be overcome by targeting BCL-XL in chronic myeloid leukemia

Cited by 26 publications

References 45 publications

Identification of key candidate targets and pathways for the targeted treatment of leukemia stem cells of chronic myelogenous leukemia using bioinformatics analysis

Identification of key candidate targets and pathways for the targeted treatment of leukemia stem cells of chronic myelogenous leukemia using bioinformatics analysis

The effect of miR-146a on STAT1 expression and apoptosis in acute lymphoblastic leukemia Jurkat cells

The Role of MYC and PP2A in the Initiation and Progression of Myeloid Leukemias

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