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E3 ubiquitin ligase Cbl-b activates the p53 pathway by targeting Siva1, a negative regulator of ARF, in FLT3 inhibitor-resistant acute myeloid leukemia

Leukemia volume 31, pages 502–505 (2017)Cite this article

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Previous clinical studies have shown that the presence of receptor tyrosine kinase (RTK) FLT3 with activating mutation, FLT3-ITD (internal tandem duplication), translates into poor prognosis in acute myeloid leukemia (AML).1 Several tyrosine kinase inhibitors (TKIs) of constitutively active FLT3 have been developed and tested in clinical trials.1 So far, these small molecule inhibitors have resulted in only modest improvement in AML patients because of, in part, the presence of leukemic blasts showing resistance against FLT3 inhibitors.2 Thus, devising an improved therapeutic strategy to overcome AML resistance to FLT3 inhibitors could improve the likelihood of achieving long-term survival of AML patients.

Tumor suppressor p53 is a critical gatekeeper for cell growth and division, and regulates a large number of downstream targets in response to various oncogenes and genotoxic stresses, ultimately suppressing tumorigenesis.3 Although mutations in the tumor suppressor p53 gene (TP53) are found in only about 5–10% of AML patients, inactivation of wild-type p53 protein frequently occurs through overexpression of its negative regulatory molecule, murine double minute 2 (MDM2), which targets p53 for ubiquitin-mediated degradation.3 On genotoxic stimuli such as irradiation, p53 is phosphorylated and the interaction between p53 and MDM2 is blocked, which leads to an increased level of p53 and eventually inhibition of the growth of tumor cells. Recent studies have shown that FLT3-ITD blocks p53 activation in AML, and restoration of p53 activities sensitizes AML blasts to FLT3 inhibitor treatment.4, 5 In addition, BA/F3 cells expressing FLT3-ITD (BA/F3-FLT3-ITD) were resistant to FLT3 inhibitor PKC412 on being transfected with lentivirus encoding shRNA targeting p53.4 This suggests that FLT3-ITD+ AML cells acquire resistance to FLT3 inhibitors, at least in part, by inactivation of p53, which provides a rationale to target p53 and its regulatory network for overcoming AML resistance to FLT3 inhibitors.

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Acknowledgements

We thank Drs James D Griffin (Dana-Farber Cancer Institute, Boston, MA, USA) and Christian Thiede (TU Dresden, Germany) for providing MOLM13-R-PKC412 and MV4-11 R-PKC412 AML cell lines, respectively. We also thank the OSUCCC Leukemia Tissue Bank Shared Resource for providing AML patient samples. This work was supported by the National Cancer Institute grants (CA016058, CA09338, CA031946, CA140158, CA89341, R35 CA210087 to MAC and CA138744 to SDB).

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Authors and Affiliations

  1. Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA

    I-K Park, S D Baker & M A Caligiuri

  2. Division of Pharmaceutics, College of Pharmacy,

    I-K Park & S D Baker

  3. The Ohio State University, Columbus, O, H, USA

    I-K Park & S D Baker

  4. Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA

    W Blum & M A Caligiuri

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  1. I-K Park
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Correspondence to M A Caligiuri.

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Park, IK., Blum, W., Baker, S. et al. E3 ubiquitin ligase Cbl-b activates the p53 pathway by targeting Siva1, a negative regulator of ARF, in FLT3 inhibitor-resistant acute myeloid leukemia. Leukemia 31, 502–505 (2017). https://doi.org/10.1038/leu.2016.293

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