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

Rodríguez, Sónia; Abundis, Christina; Boccalatte, Francesco; Mehrotra, Purvi; Chiang, Mark Y.; Yui, Mary A.; Wang, Lin; Zhang, Huajia; Zollman, Amy; Bonfim-Silva, Ricardo; Kloetgen, Andreas; Palmer, Joycelynne; Sandusky, George E.; Wunderlich, Mark; Kaplan, Mark H.; Mulloy, James C.; Marcucci, Guido; Aifantis, Iannis; Cardoso, Angelo A.; Carlesso, Nadia

doi:10.1038/s41375-019-0653-z

Cited by 31 publications

(23 citation statements)

References 47 publications

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“…IL-7, produced in the bone marrow and thymus, is a major microenvironmental signal promoting T-ALL cell expansion [26,39,[42][43][44]48,[55][56][57]. We have previously found that CK2 activity is mandatory for optimal IL-7/IL-7R-mediated signaling.…”

Section: Discussionmentioning

confidence: 99%

Clinical-Grade Peptide-Based Inhibition of CK2 Blocks Viability and Proliferation of T-ALL Cells and Counteracts IL-7 Stimulation and Stromal Support

Perera

Melão

Ramón

et al. 2020

Cancers

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Despite remarkable advances in the treatment of T-cell acute lymphoblastic leukemia (T-ALL), relapsed cases are still a major challenge. Moreover, even successful cases often face long-term treatment-associated toxicities. Targeted therapeutics may overcome these limitations. We have previously demonstrated that casein kinase 2 (CK2)-mediated phosphatase and tensin homologue (PTEN) posttranslational inactivation, and consequent phosphatidylinositol 3-kinase (PI3K)/Akt signaling hyperactivation, leads to increased T-ALL cell survival and proliferation. We also revealed the existence of a crosstalk between CK2 activity and the signaling mediated by interleukin 7 (IL-7), a critical leukemia-supportive cytokine. Here, we evaluated the impact of CIGB-300, a the clinical-grade peptide-based CK2 inhibitor CIGB-300 on T-ALL biology. We demonstrate that CIGB-300 decreases the viability and proliferation of T-ALL cell lines and diagnostic patient samples. Moreover, CIGB-300 overcomes IL-7-mediated T-ALL cell growth and viability, while preventing the positive effects of OP9-delta-like 1 (DL1) stromal support on leukemia cells. Signaling and pull-down experiments indicate that the CK2 substrate nucleophosmin 1 (B23/NPM1) and CK2 itself are the molecular targets for CIGB-300 in T-ALL cells. However, B23/NPM1 silencing only partially recapitulates the anti-leukemia effects of the peptide, suggesting that CIGB-300-mediated direct binding to CK2, and consequent CK2 inactivation, is the mechanism by which CIGB-300 downregulates PTEN S380 phosphorylation and inhibits PI3K/Akt signaling pathway. In the context of IL-7 stimulation, CIGB-300 blocks janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway in T-ALL cells. Altogether, our results strengthen the case for anti-CK2 therapeutic intervention in T-ALL, demonstrating that CIGB-300 (given its ability to circumvent the effects of pro-leukemic microenvironmental cues) may be a valid tool for clinical intervention in this aggressive malignancy.

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Section: Discussionmentioning

confidence: 99%

Clinical-Grade Peptide-Based Inhibition of CK2 Blocks Viability and Proliferation of T-ALL Cells and Counteracts IL-7 Stimulation and Stromal Support

Perera

Melão

Ramón

et al. 2020

Cancers

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“…These findings suggest that SKP2 and FBXL12 are both required for T cell development in an identical and additive manner as result of their targeting the same protein. Consideration of the potential of inhibition of the SKP2-p27 KIP1 pathway for the treatment of T cell leukemia [252] should thus take into account the role of FBXL12.…”

Section: P27 Kip1mentioning

confidence: 99%

F-Box Proteins and Cancer

Yumimoto

Yamauchi

Nakayama

2020

Cancers

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Controlled protein degradation is essential for the operation of a variety of cellular processes including cell division, growth, and differentiation. Identification of the relations between ubiquitin ligases and their substrates is key to understanding the molecular basis of cancer development and to the discovery of novel targets for cancer therapeutics. F-box proteins function as the substrate recognition subunits of S-phase kinase-associated protein 1 (SKP1)−Cullin1 (CUL1)−F-box protein (SCF) ubiquitin ligase complexes. Here, we summarize the roles of specific F-box proteins that have been shown to function as tumor promoters or suppressors. We also highlight proto-oncoproteins that are targeted for ubiquitylation by multiple F-box proteins, and discuss how these F-box proteins are deployed to regulate their cognate substrates in various situations.

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“…Standard retrovirus infections were performed as previously report with slight modifications ( Kobayashi et al, 2017 ; Rodriguez et al, 2020 ). YS or P-Sp derived hematopoietic cells, 6–7 days after co-culture with OP9-DL1, were plated at 2.5 × 10 5 cells per well on a 24 well plate the day before viral transduction.…”

Section: Methodsmentioning

confidence: 99%

The Earliest T-Precursors in the Mouse Embryo Are Susceptible to Leukemic Transformation

Ding

Cardoso

Yoshimoto

et al. 2021

Front. Cell Dev. Biol.

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Acute lymphoblastic leukemia (ALL) is the most common malignancy in pediatric patients. About 10–15% of pediatric ALL belong to T-cell ALL (T-ALL), which is characterized by aggressive expansion of immature T-lymphoblasts and is categorized as high-risk leukemia. Leukemia initiating cells represent a reservoir that is responsible for the initiation and propagation of leukemia. Its perinatal origin has been suggested in some childhood acute B-lymphoblastic and myeloblastic leukemias. Therefore, we hypothesized that child T-ALL initiating cells also exist during the perinatal period. In this study, T-ALL potential of the hematopoietic precursors was found in the para-aortic splanchnopleura (P-Sp) region, but not in the extraembryonic yolk sac (YS) of the mouse embryo at embryonic day 9.5. We overexpressed the Notch intracellular domain (NICD) in the P-Sp and YS cells and transplanted them into lethally irradiated mice. NICD-overexpressing P-Sp cells rapidly developed T-ALL while YS cells failed to display leukemia propagation despite successful NICD induction. These results suggest a possible role of fetal-derived T-cell precursors as leukemia-initiating cells.

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

Cited by 31 publications

References 47 publications

Clinical-Grade Peptide-Based Inhibition of CK2 Blocks Viability and Proliferation of T-ALL Cells and Counteracts IL-7 Stimulation and Stromal Support

Clinical-Grade Peptide-Based Inhibition of CK2 Blocks Viability and Proliferation of T-ALL Cells and Counteracts IL-7 Stimulation and Stromal Support

F-Box Proteins and Cancer

The Earliest T-Precursors in the Mouse Embryo Are Susceptible to Leukemic Transformation

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