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Therapeutic targeting of the E3 ubiquitin ligase SKP2 in T-ALL

Rodriguez, Sonia and Abundis, Christina and Boccalatte, Francesco and Mehrotra, Purvi and Chiang, Mark Y. and Yui, Mary A. and Wang, Lin and Zhang, Huajia and Zollman, Amy and Bonfim-Silva, Ricardo and Kloetgen, Andreas and Palmer, Joycelynne and Sandusky, George and Wunderlich, Mark and Kaplan, Mark H. and Mulloy, James C. and Marcucci, Guido and Aifantis, Iannis and Cardoso, Angelo A. and Carlesso, Nadia (2020) Therapeutic targeting of the E3 ubiquitin ligase SKP2 in T-ALL. Leukemia, 34 (5). pp. 1241-1252. ISSN 0887-6924. PMCID PMC7192844. https://resolver.caltech.edu/CaltechAUTHORS:20191203-083909065

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Abstract

Timed degradation of the cyclin-dependent kinase inhibitor p27^(Kip1) by the E3 ubiquitin ligase F-box protein SKP2 is critical for T-cell progression into cell cycle, coordinating proliferation and differentiation processes. SKP2 expression is regulated by mitogenic stimuli and by Notch signaling, a key pathway in T-cell development and in T-cell acute lymphoblastic leukemia (T-ALL); however, it is not known whether SKP2 plays a role in the development of T-ALL. Here, we determined that SKP2 function is relevant for T-ALL leukemogenesis, whereas is dispensable for T-cell development. Targeted inhibition of SKP2 by genetic deletion or pharmacological blockade markedly inhibited proliferation of human T-ALL cells in vitro and antagonized disease in vivo in murine and xenograft leukemia models, with little effect on normal tissues. We also demonstrate a novel feed forward feedback loop by which Notch and IL-7 signaling cooperatively converge on SKP2 induction and cell cycle activation. These studies show that the Notch/SKP2/p27^(Kip1) pathway plays a unique role in T-ALL development and provide a proof-of-concept for the use of SKP2 as a new therapeutic target in T-cell acute lymphoblastic leukemia (T-ALL).


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1038/s41375-019-0653-zDOIArticle
https://rdcu.be/bYcc3PublisherFree ReadCube access
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7192844PubMed CentralArticle
ORCID:
AuthorORCID
Mehrotra, Purvi0000-0001-9369-5013
Yui, Mary A.0000-0002-3136-2181
Additional Information:© The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Received 23 April 2019; Revised 18 October 2019; Accepted 13 November 2019; Published 26 November 2019. We thank the Flow Cytometry, In Vivo Therapeutics and Optical Imaging cores supported by Indiana Center for Excellence in Molecular Hematology (National Insitute of Diabetes and Digestive and Kidney Diseases grant P30 DK090948), and the ARC Core at City of Hope supported by the National Cancer Institute of the National Institutes of Health under grant number P30CA033572. Part of this work was supported by the Grace M. Showalter Trust (064727-00002B, SR). The authors declare that they have no conflict of interest.
Funders:
Funding AgencyGrant Number
NIHP30 DK090948
NIHP30CA033572
Grace M. Showalter Trust064727-00002B
Subject Keywords:Acute lymphocytic leukaemia; Targeted therapies
Issue or Number:5
PubMed Central ID:PMC7192844
Record Number:CaltechAUTHORS:20191203-083909065
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20191203-083909065
Official Citation:Rodriguez, S., Abundis, C., Boccalatte, F. et al. Therapeutic targeting of the E3 ubiquitin ligase SKP2 in T-ALL. Leukemia 34, 1241–1252 (2020). https://doi.org/10.1038/s41375-019-0653-z
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:100161
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:04 Dec 2019 18:15
Last Modified:11 May 2020 16:05

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