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Molecular Cancer Research
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Cancer Genes and Networks

FBW7 Inhibits Myeloid Differentiation in Acute Myeloid Leukemia via GSK3-Dependent Ubiquitination of PU.1

Mukul Mishra, Gatha Thacker, Akshay Sharma, Anil Kumar Singh, Vishal Upadhyay, Sabyasachi Sanyal, Shailendra Prasad Verma, Anil Kumar Tripathi, Madan Lal Brahma Bhatt and Arun Kumar Trivedi
Mukul Mishra
1Division of Cancer Biology, CSIR-Central Drug Research Institute, Lucknow, UP, India.
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Gatha Thacker
1Division of Cancer Biology, CSIR-Central Drug Research Institute, Lucknow, UP, India.
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Akshay Sharma
1Division of Cancer Biology, CSIR-Central Drug Research Institute, Lucknow, UP, India.
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Anil Kumar Singh
1Division of Cancer Biology, CSIR-Central Drug Research Institute, Lucknow, UP, India.
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Vishal Upadhyay
1Division of Cancer Biology, CSIR-Central Drug Research Institute, Lucknow, UP, India.
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Sabyasachi Sanyal
2Biochemistry Division, CSIR-Central Drug Research Institute, Lucknow, UP, India.
3Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, UP, India.
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Shailendra Prasad Verma
4King George's Medical University, Lucknow, UP, India.
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  • ORCID record for Shailendra Prasad Verma
Anil Kumar Tripathi
4King George's Medical University, Lucknow, UP, India.
5Ram Manohar Lohia Institute of Medical Sciences (RMLIMS), UP, Lucknow, India.
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Madan Lal Brahma Bhatt
4King George's Medical University, Lucknow, UP, India.
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Arun Kumar Trivedi
1Division of Cancer Biology, CSIR-Central Drug Research Institute, Lucknow, UP, India.
3Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, UP, India.
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  • For correspondence: arun3vedi@cdri.res.in
DOI: 10.1158/1541-7786.MCR-20-0268 Published February 2021
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Abstract

Glycogen synthase kinase 3β (GSK3β), an ubiquitously expressed serine/threonine kinase is reported to be overexpressed and hyperactivated in cancers including acute myeloid leukemia (AML) where it promotes self-renewal, growth, and survival of AML cells. Therefore, GSK3β inhibition results in AML cell growth inhibition and myeloid differentiation. Here we identified master transcription factor PU.1 of monocyte–macrophage differentiation pathway as potential GSK3β target. We demonstrate that GSK3β phosphorylates PU.1 at Ser41 and Ser140 leading to its recognition and subsequent ubiquitin-mediated degradation by E3 ubiquitin ligase FBW7. This GSK3-dependent degradation of PU.1 by FBW7 inhibited monocyte–macrophage differentiation. We further showed that a phospho-deficient PU.1 mutant (PU.1-S41, S140A) neither bound to FBW7 nor was degraded by it. Consequently, PU.1-S41, S140A retained its transactivation, DNA-binding ability and promoted monocyte–macrophage differentiation of U937 cells even without phorbol 12-myristate 13-acetate (PMA) treatment. We further showed that FBW7 overexpression inhibited both PMA as well as M-CSF–induced macrophage differentiation of myeloid cell lines and peripheral blood mononuclear cells (PBMC) from healthy volunteers, respectively. Contrarily, FBW7 depletion promoted differentiation of these cells even without any inducer suggesting for a robust role of GSK3β–FBW7 axis in negatively regulating myeloid differentiation. Furthermore, we also recapitulated these findings in PBMCs isolated from patients with leukemia where FBW7 overexpression markedly inhibited endogenous PU.1 protein levels. In addition, PBMCs also showed enhanced differentiation when treated with M-CSF and GSK3 inhibitor (SB216763) together compared with M-CSF treatment alone.

Implications: Our data demonstrate a plausible mechanism behind PU.1 restoration and induction of myeloid differentiation upon GSK3β inhibition and further substantiates potential of GSK3β as a therapeutic target in AML.

Footnotes

  • Mol Cancer Res 2021;19:261–73

  • Received March 23, 2020.
  • Revision received July 17, 2020.
  • Accepted November 9, 2020.
  • Published first November 13, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Research: 19 (2)
February 2021
Volume 19, Issue 2
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FBW7 Inhibits Myeloid Differentiation in Acute Myeloid Leukemia via GSK3-Dependent Ubiquitination of PU.1
Mukul Mishra, Gatha Thacker, Akshay Sharma, Anil Kumar Singh, Vishal Upadhyay, Sabyasachi Sanyal, Shailendra Prasad Verma, Anil Kumar Tripathi, Madan Lal Brahma Bhatt and Arun Kumar Trivedi
Mol Cancer Res February 1 2021 (19) (2) 261-273; DOI: 10.1158/1541-7786.MCR-20-0268

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FBW7 Inhibits Myeloid Differentiation in Acute Myeloid Leukemia via GSK3-Dependent Ubiquitination of PU.1
Mukul Mishra, Gatha Thacker, Akshay Sharma, Anil Kumar Singh, Vishal Upadhyay, Sabyasachi Sanyal, Shailendra Prasad Verma, Anil Kumar Tripathi, Madan Lal Brahma Bhatt and Arun Kumar Trivedi
Mol Cancer Res February 1 2021 (19) (2) 261-273; DOI: 10.1158/1541-7786.MCR-20-0268
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