PRL3 enhances T-cell acute lymphoblastic leukemia growth through suppressing T-cell signaling pathways and apoptosis

Garcia, Elaine G.; Veloso, Alexandra; Oliveira, Mariana L.; Allen, James H.; Loontiens, Siebe; Brunson, Dalton C.; Do, Daniel; Yan, Chuan; Morris, Robert T.; Iyer, Sowmya; Garcia, Sara P.; Iftimia, Nicolae; Loocke, Wouder Van; Matthijssens, Filip; McCarthy, Karin M.; Barata, João T.; Speleman, Franki; Taghon, Tom; Gutiérrez, Alejandro; Vlierberghe, Pieter Van; Haas, Wilhelm; Blackburn, Jessica S.; Langenau, Dm M.

doi:10.1038/s41375-020-0937-3

Cited by 16 publications

(14 citation statements)

References 49 publications

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“…Our study also found that NOTCH1 was activated as a tumor suppressor after treatment with CBL0137. It is now widely recognized that the MYC transcription factor is a dominant oncogenic driver in a majority of human T-ALL and is often activated downstream of NOTCH1 [ 71 ], and targeting the NOTCH/MYC pathway can lead to cell death by increasing the apoptosis of tumor cells. In summary, the anticancer mechanisms of CBL0137 that we have shown are interrelated.…”

Section: Discussionmentioning

confidence: 99%

The FACT-targeted drug CBL0137 enhances the effects of rituximab to inhibit B-cell non-Hodgkin’s lymphoma tumor growth by promoting apoptosis and autophagy

et al. 2023

Cell Commun Signal

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Background Aggressive B-cell non-Hodgkin’s lymphoma (B-NHL) patients often develop drug resistance and tumor recurrence after conventional immunochemotherapy, for which new treatments are needed. Methods We investigated the antitumor effects of CBL0137. In vitro, cell proliferation was assessed by CCK-8 and colony formation assay. Flow cytometry was performed to analyze cell cycle progression, apoptosis, mitochondrial depolarization, and reactive oxygen species (ROS) production. Autophagy was detected by transmission electron microscopy and mGFP-RFP-LC3 assay, while western blotting was employed to detect proteins involved in apoptosis and autophagy. RNA-sequencing was conducted to analyze the transcription perturbation after CBL0137 treatment in B-NHL cell lines. Finally, the efficacy and safety of CBL0137, rituximab, and their combination were tested in vivo. Results CBL0137, a small molecule anticancer agent that has significant antitumor effects in B-NHL. CBL0137 sequesters the FACT (facilitates chromatin transcription) complex from chromatin to produce cytotoxic effects in B-NHL cells. In addition, we discovered novel anticancer mechanisms of CBL0137. CBL0137 inhibited human B-NHL cell proliferation by inducing cell cycle arrest in S phase via the c-MYC/p53/p21 pathway. Furthermore, CBL0137 triggers ROS generation and induces apoptosis and autophagy in B-NHL cells through the ROS-mediated PI3K/Akt/mTOR and MAPK signaling pathways. Notably, a combination of CBL0137 and rituximab significantly suppressed B-NHL tumor growth in subcutaneous models, consistent with results at the cellular level in vitro. Conclusions CBL0137 has potential as a novel approach for aggressive B-NHL, and its combination with rituximab can provide new therapeutic options for patients with aggressive B-NHL.

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Section: Discussionmentioning

confidence: 99%

The FACT-targeted drug CBL0137 enhances the effects of rituximab to inhibit B-cell non-Hodgkin’s lymphoma tumor growth by promoting apoptosis and autophagy

et al. 2023

Cell Commun Signal

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“…The Notch signaling pathway is a functional pathway that controls cell survival, proliferation, differentiation, apoptosis, migration, and invasion, and is involved in the determination of cell biological functions in both normal and pathological tissues 19 – 21 . Several studies have revealed the regulatory effect of the Notch signaling pathway in multiple cancers, including breast cancer 22 , colorectal cancer 23 , acute myeloid leukemia 24 , and ALL 25 . Indeed, Notch signaling pathway inhibitors, such as gamma-secretase inhibitors, have been considered as promising tools for cancer therapy 24 , 26 .…”

Section: Discussionmentioning

confidence: 99%

Proteomic profiling of plasma exosomes from patients with B-cell acute lymphoblastic leukemia

Zhu

Cheng

et al. 2022

Sci Rep

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We aimed to comprehensively investigate the proteomic profile and underlying biological function of exosomal proteins associated with B-cell acute lymphoblastic leukemia. Exosomes were isolated from plasma samples collected from five patients with B-ALL and five healthy individuals, and their protein content was quantitatively analyzed by liquid chromatography with tandem mass spectrometry. A total of 342 differentially expressed proteins were identified in patients with B-ALL. The DEPs were mainly associated with protein metabolic processes and protein activity regulation and were significantly enriched in the Notch and autophagy pathways. Furthermore, we found that ADAM17 and ATG3 were upregulated in patients with B-ALL and enriched in the Notch and autophagy pathways, respectively. Further western blot analysis of exosomes collected from additional 18 patients with B-ALL and 10 healthy controls confirmed that both ADAM17 and ATG3 were overexpressed in exosomes derived from patients with B-ALL (p < 0.001). The areas under the curves of ADAM17 and ATG3 were 0.989 and 0.956, respectively, demonstrating their diagnostic potential. In conclusion, ADAM17 and ATG3 in plasma-derived exosomes may contribute to the progression of B-ALL by regulating the Notch and autophagy pathways. Hence, these proteins may represent valuable diagnostic biomarkers and therapeutic targets for B-ALL.

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“…1 T-ALL, derived from T cells, accumulates genomic or epigenetic alterations that accelerate transformation. 2 The recommended pediatric therapy for ALL includes a combination of vincristine, anthracyclines, and steroids. 3 Once administered with suitable treatments, almost all patients with T-ALL are likely to achieve complete remission, although the rates of survival and relapse within 5 years remain unsatisfactory.…”

Section: Introductionmentioning

confidence: 99%

“…ALL can be subdivided into two sub‐types (T‐ALL or B‐ALL) according to the origin of the cancer cells 1 . T‐ALL, derived from T cells, accumulates genomic or epigenetic alterations that accelerate transformation 2 . The recommended pediatric therapy for ALL includes a combination of vincristine, anthracyclines, and steroids 3 .…”

Section: Introductionmentioning

confidence: 99%

The depletion of Circ‐PRKDC enhances autophagy and apoptosis in T‐cell acute lymphoblastic leukemia via microRNA‐653‐5p/Reelin mediation of the PI3K/AKT/mTOR signaling pathway

Zhang

Fang

et al. 2021

The Kaohsiung J of Med Scie

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A range of circular (Circ) RNAs have been demonstrated to be of therapeutic significance for the treatment of acute lymphoblastic leukemia (ALL). Here, we investigated the mechanisms underlying the action of Circ-PRKDC and the microRNA-653-5p/ Reelin (miR-653-5p/RELN) axis in T-cell ALL (T-ALL).Clinical specimens were obtained from patients with T-ALL (n = 39) and healthy controls (n = 30). In each specimen, we determined the expression levels of Circ-PRKDC, miR-653-5p, and RELN. Human T-ALL cells (Jurkat) were transfected with Circ-PRKDC-or miR-653-5p-related sequences to investigate cell proliferation, apoptosis, and autophagy. We also determined the levels of Circ-PRKDC, miR-653-5p, RELN, and signaling proteins related to phosphoinositide 3-kinase (PI3K), AKT, and mammalian target of rapamycin (mTOR). Finally, we decoded the interactions between Circ-PRKDC, miR-653-5p, and RELN. The expression levels of Circ-PRKDC and RELN were upregulated in T-ALL tissues and cells while the levels of miR-653-5p were downregulated. Thereafter, then silencing of Circ-PRKDC, or the enforced expression of miR-653-5p, repressed the expression of RELN and the activation of the PI3K/AKT/mTOR signaling pathway, thus enhancing cell autophagy and apoptosis, and disrupting cell proliferation. Circ-PRKDC acted a sponge for miR-653-5p while miR-653-5p targeted RELN. The knockdown of miR-653-5p abrogated the silencing of Circ-PRKDCinduced effects in T-ALL cells. The depletion of Circ-PRKDC elevated miR-653-5p to silence RELN-mediated PI3K/AKT/mTOR signaling activation, thereby enhancing autophagy and apoptosis in T-ALL cells.

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PRL3 enhances T-cell acute lymphoblastic leukemia growth through suppressing T-cell signaling pathways and apoptosis

Cited by 16 publications

References 49 publications

The FACT-targeted drug CBL0137 enhances the effects of rituximab to inhibit B-cell non-Hodgkin’s lymphoma tumor growth by promoting apoptosis and autophagy

The FACT-targeted drug CBL0137 enhances the effects of rituximab to inhibit B-cell non-Hodgkin’s lymphoma tumor growth by promoting apoptosis and autophagy

Proteomic profiling of plasma exosomes from patients with B-cell acute lymphoblastic leukemia

The depletion of Circ‐PRKDC enhances autophagy and apoptosis in T‐cell acute lymphoblastic leukemia via microRNA‐653‐5p/Reelin mediation of the PI3K/AKT/mTOR signaling pathway

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