Therapeutic targeting of the E3 ubiquitin ligase SKP2 in T-ALL.
Leukemia
; 34(5): 1241-1252, 2020 05.
Article
in En
| MEDLINE
| ID: mdl-31772299
ABSTRACT
Timed degradation of the cyclin-dependent kinase inhibitor p27Kip1 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/p27Kip1 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).
Full text:
1
Database:
MEDLINE
Main subject:
Gene Expression Regulation, Neoplastic
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Apoptosis
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S-Phase Kinase-Associated Proteins
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Protein Kinase Inhibitors
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Cell Proliferation
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Limits:
Animals
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Female
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Humans
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Male
Language:
En
Year:
2020
Type:
Article