c-Myc inhibition decreases CIP2A and reduces BCR-ABL1 tyrosine kinase activity in chronic myeloid leukemia

Lucas, Claire; Harris, Robert J.; Giannoudis, Athina; Clark, Richard E.

doi:10.3324/haematol.2014.115691

Cited by 15 publications

(15 citation statements)

References 11 publications

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“…c-Myc in cells (Lucas et al, 2015;Muller et al, 2014;Wang et al, 2014;Zirath et al, 2013). We found that c-Myc inhibition blocked the let-7adf cluster's regulatory effects on the expression of Slc1a5 and Gls ( Figure 6E), and on glutaminolysis, indicated by comparable levels of glutamine consumption and ammonium production in B cells (Figures 6F and 6G).…”

Section: Comprehensive Repression Of All Let-7 Mirnas Enhances Igm Prmentioning

confidence: 80%

Let-7 Suppresses B Cell Activation through Restricting the Availability of Necessary Nutrients

et al. 2018

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Section: Comprehensive Repression Of All Let-7 Mirnas Enhances Igm Prmentioning

confidence: 80%

Let-7 Suppresses B Cell Activation through Restricting the Availability of Necessary Nutrients

et al. 2018

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“…Furthermore we have recently demonstrated that c-Myc inhibition the small molecule inhibitor 10058-F4 leads to a reduction in both CIP2A and BCR-ABL tyrosine kinase activity. 53 Moreover, E2F1 inhibition results in a decrease in both CIP2A and c-Myc. These data suggest that disruption of the CIP2A/c-Myc/E2F1 interaction is important for the reactivation of PP2A and suppression of BCR-ABL.…”

Section: Discussionmentioning

confidence: 99%

Second generation tyrosine kinase inhibitors prevent disease progression in high-risk (high CIP2A) chronic myeloid leukaemia patients

et al. 2015

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High cancerous inhibitor of PP2A (CIP2A) protein levels at diagnosis of chronic myeloid leukaemia (CML) are predictive of disease progression in imatinib-treated patients. It is not known whether this is true in patients treated with second generation tyrosine kinase inhibitors (2G TKI) from diagnosis, and whether 2G TKIs modulate the CIP2A pathway. Here, we show that patients with high diagnostic CIP2A levels who receive a 2G TKI do not progress, unlike those treated with imatinib (P=<0.0001). 2G TKIs induce more potent suppression of CIP2A and c-Myc than imatinib. The transcription factor E2F1 is elevated in high CIP2A patients and following 1 month of in vivo treatment 2G TKIs suppress E2F1 and reduce CIP2A; these effects are not seen with imatinib. Silencing of CIP2A, c-Myc or E2F1 in K562 cells or CML CD34+ cells reactivates PP2A leading to BCR-ABL suppression. CIP2A increases proliferation and this is only reduced by 2G TKIs. Patients with high CIP2A levels should be offered 2G TKI treatment in preference to imatinib. 2G TKIs disrupt the CIP2A/c-Myc/E2F1 positive feedback loop, leading to lower disease progression risk. The data supports the view that CIP2A inhibits PP2Ac, stabilising E2F1, creating a CIP2A/c-Myc/E2F1 positive feedback loop, which imatinib cannot overcome.

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“…Additionally, CIP2A mRNA and protein content is regulated by MYC, creating a positive feedback loop between the two oncogenes in cancer [95]. By inhibiting MYC, by treating the cells with an inhibitor of MYC interaction with its partner MAX through the basic-helix-loop-helix-leucine zipper domain, 10058-F4 [120], Lucas et al demonstrated that the levels of CIP2A and SET could be dramatically reduced, confirming once again that studying the inhibition of MYC is worth it [121].…”

Section: Arpp19mentioning

confidence: 94%

“…Several molecules have been described as MYC inhibitors, although none of them are used in the clinic. The 10058-F4, which prevents the interaction of MYC with MAX, used in several preclinical studies, was able to reduce BCR-ABL kinase activity and CIP2A expression in CML patients [121]. In AML cells, it was reported that 10058-F4 inhibits growth, induces cell cycle arrest, and differentiation [126].…”

Section: Targeting the Myc/pp2a Axis In Leukemiamentioning

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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c-Myc inhibition decreases CIP2A and reduces BCR-ABL1 tyrosine kinase activity in chronic myeloid leukemia

Cited by 15 publications

References 11 publications

Let-7 Suppresses B Cell Activation through Restricting the Availability of Necessary Nutrients

Let-7 Suppresses B Cell Activation through Restricting the Availability of Necessary Nutrients

Second generation tyrosine kinase inhibitors prevent disease progression in high-risk (high CIP2A) chronic myeloid leukaemia patients

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

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