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).
Highlights
Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer and second leading cause of childhood death [1]
Skp2 expression was dynamically regulated during thymocyte development, with higher levels of expression associated with high proliferative status, especially at post-β-selection double negative (DN; CD4−CD8−) stages, DN3B and DN4; and the immature CD8+ single positive (ISP) stage (Fig. S1A; right panel; reviewed in [21])
We addressed the role of SKP2 in normal and malignant T-cells and showed that SKP2 is dispensable for normal thymocyte development but plays an active role in T-cell leukemogenesis
Summary
Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer and second leading cause of childhood death [1]. Despite marked clinical advances in the treatment of the T-cell subtype of ALL (T-ALL), about 30% of patients experience relapse or refractory disease, which is associated with poor prognosis. Multiple oncogenic signaling mechanisms are involved in T-ALL, including hyperactivation of the PI3K-AKT pathway, deletion of key cell cycle inhibitors, ectopic expression of transcription factors, and hyperactivation of the Notch signaling pathway [2]. The identification of activating mutations in the majority of T-ALL patients places Notch signaling as a central player in T-cell leukemogenesis in both children and adults [3, 4], its therapeutic targeting poses significant challenges due to its important
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