Notch3 contributes to T-cell leukemia growth via regulation of the unfolded protein response

Giuli, Maria Valeria; Diluvio, Giulia; Giuliani, Eugenia; Franciosa, Giulia; Magno, Laura Di; Pignataro, Maria Gemma; Tottone, Luca; Nicoletti, Carmine; Besharat, Zein Mersini; Peruzzi, Giovanna; Pelullo, Maria; Palermo, Rocco; Canettieri, Gianluca; Talora, Claudio; d’Amati, Giulia; Bellavia, Diana; Screpanti, Isabella; Checquolo, Saula

doi:10.1038/s41389-020-00279-7

Cited by 14 publications

(11 citation statements)

References 65 publications

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“…First, we used the Notch1-activated KE-37 cell line, being Notch1 a frequent target of oncogenic gain-of-function mutations in T-ALL patients ( 11 ). Interestingly, KE-37 cells are GSI resistant and Notch3 negative ( 42 ) and express intracellular IL-6 ( Supplementary Figure S5A ). The harvested PBMCs/KE-37 coculture samples reveal a significant increase of CD14 + HLA-DR low/neg “putative” MDSCs, both in percentages ( Figures 7A, B , left panel) and absolute numbers ( Figure 7B , right panel), when compared with samples of autologous PBMCs cultured alone.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, we performed experiments above with the Notch3-activated T-ALL cell line, TALL-1 ( 31 ) that is IL-6 + ( Supplementary Figure S5A ) and Notch1-negative ( 42 ). TALL-1 cells promote the induction of suppressive MDSCs ( Supplementary Figures S5B–D ) that is inhibited by exposure to GSIs or anti-IL-6 antibodies ( Supplementary Figures S5E, F , respectively).…”

Section: Resultsmentioning

confidence: 99%

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Notch-Signaling Deregulation Induces Myeloid-Derived Suppressor Cells in T-Cell Acute Lymphoblastic Leukemia

et al. 2022

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Notch receptors deeply influence T-cell development and differentiation, and their dysregulation represents a frequent causative event in “T-cell acute lymphoblastic leukemia” (T-ALL). “Myeloid-derived suppressor cells” (MDSCs) inhibit host immune responses in the tumor environment, favoring cancer progression, as reported in solid and hematologic tumors, with the notable exception of T-ALL. Here, we prove that Notch-signaling deregulation in immature T cells promotes CD11b+Gr-1+ MDSCs in the Notch3-transgenic murine model of T-ALL. Indeed, aberrant T cells from these mice can induce MDSCs in vitro, as well as in immunodeficient hosts. Conversely, anti-Gr1-mediated depletion of MDSCs in T-ALL-bearing mice reduces proliferation and expansion of malignant T cells. Interestingly, the coculture with Notch-dependent T-ALL cell lines, sustains the induction of human CD14+HLA-DRlow/neg MDSCs from healthy-donor PBMCs that are impaired upon exposure to gamma-secretase inhibitors. Notch-independent T-ALL cells do not induce MDSCs, suggesting that Notch-signaling activation is crucial for this process. Finally, in both murine and human models, IL-6 mediates MDSC induction, which is significantly reversed by treatment with neutralizing antibodies. Overall, our results unveil a novel role of Notch-deregulated T cells in modifying the T-ALL environment and represent a strong premise for the clinical assessment of MDSCs in T-ALL patients.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Notch-Signaling Deregulation Induces Myeloid-Derived Suppressor Cells in T-Cell Acute Lymphoblastic Leukemia

et al. 2022

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“…Leukemia is characterized by the accumulation of gene mutations and chromosomal translocations that the encoding proteins are frequently prone to misfolding ( 23 , 44 , 45 ). It has been reported that sustained UPR exists in multiple leukemia types and plays a vital role in disease progression and therapeutic resistance ( 19 , 20 , 46 – 48 ). Thus, targeting ER stress and UPR mechanisms represents attractive therapeutic options to the leukemia treatment ( 49 – 53 ).…”

Section: Discussionmentioning

confidence: 99%

3-Ketodihydrosphingosine reductase maintains ER homeostasis and unfolded protein response in leukemia

et al. 2021

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Sphingolipids and their metabolic pathways have been implicated in disease development and therapeutic response; however, the detailed mechanisms remain unclear. Using a sphingolipid network focused CRISPR/Cas9 library screen, we identified an endoplasmic reticulum (ER) enzyme, 3-Ketodihydrosphingosine reductase (KDSR), to be essential for leukemia cell maintenance. Loss of KDSR led to apoptosis, cell cycle arrest, and aberrant ER structure. Transcriptomic analysis revealed the indispensable role of KDSR in maintaining the unfolded protein response (UPR) in ER. High-density CRISPR tiling scan and sphingolipid mass spectrometry pinpointed the critical role of KDSR’s catalytic function in leukemia. Mechanistically, depletion of KDSR resulted in accumulated 3-ketodihydrosphingosine (KDS) and dysregulated UPR checkpoint proteins PERK, ATF6, and ATF4. Finally, our study revealed the synergism between KDSR suppression and pharmacologically induced ER-stress, underscoring a therapeutic potential of combinatorial targeting sphingolipid metabolism and ER homeostasis in leukemia treatment.

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“…Similarly, the natural occurring phenolic compound juglone (5-hydroxy-1,4-naphthoquinone) had anti-Notch3 activities both in in vitro and in vivo leukemia settings, thus suggesting juglonebased therapies as potential approaches for the treatment of Notch3-dependent T-ALL [346].…”

Section: Natural Compounds As Notch Signaling Modulatorsmentioning

confidence: 99%

Targeting Notch to Maximize Chemotherapeutic Benefits: Rationale, Advanced Strategies, and Future Perspectives

Zhdanovskaya

Firrincieli

Lazzari

et al. 2021

Cancers

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Notch signaling guides cell fate decisions by affecting proliferation, apoptosis, stem cell self-renewal, and differentiation depending on cell and tissue context. Given its multifaceted function during tissue development, both overactivation and loss of Notch signaling have been linked to tumorigenesis in ways that are either oncogenic or oncosuppressive, but always context-dependent. Notch signaling is critical for several mechanisms of chemoresistance including cancer stem cell maintenance, epithelial-mesenchymal transition, tumor-stroma interaction, and malignant neovascularization that makes its targeting an appealing strategy against tumor growth and recurrence. During the last decades, numerous Notch-interfering agents have been developed, and the abundant preclinical evidence has been transformed in orphan drug approval for few rare diseases. However, the majority of Notch-dependent malignancies remain untargeted, even if the application of Notch inhibitors alone or in combination with common chemotherapeutic drugs is being evaluated in clinical trials. The modest clinical success of current Notch-targeting strategies is mostly due to their limited efficacy and severe on-target toxicity in Notch-controlled healthy tissues. Here, we review the available preclinical and clinical evidence on combinatorial treatment between different Notch signaling inhibitors and existent chemotherapeutic drugs, providing a comprehensive picture of molecular mechanisms explaining the potential or lacking success of these combinations.

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Notch3 contributes to T-cell leukemia growth via regulation of the unfolded protein response

Cited by 14 publications

References 65 publications

Notch-Signaling Deregulation Induces Myeloid-Derived Suppressor Cells in T-Cell Acute Lymphoblastic Leukemia

Notch-Signaling Deregulation Induces Myeloid-Derived Suppressor Cells in T-Cell Acute Lymphoblastic Leukemia

3-Ketodihydrosphingosine reductase maintains ER homeostasis and unfolded protein response in leukemia

Targeting Notch to Maximize Chemotherapeutic Benefits: Rationale, Advanced Strategies, and Future Perspectives

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