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The Role of Notch Signaling Activation and Its Cross-Talk with Other Pathways in Hematological Malignancies

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 10669

Special Issue Editors

Prof. Dr. Emanuela Rosati

E-Mail Website
Guest Editor
Department of Medicine and Surgery, University of Perugia, Perugia, Italy
Interests: B cell biology; B cell chronic lymphocytic leukemia; Notch signaling; NOTCH mutations; Jagged ligands; cell survival/apoptosis; regulatory T cells; endoplasmic reticulum stress
Prof. Dr. Antonio F. Campese

E-Mail Website
Guest Editor
Department of Molecular Medicine, ‘Sapienza’, University of Rome, 00161 Rome, Italy
Interests: T cell development/differentiation; T cell leukemia; Notch signaling; regulatory T cells; myeloid derived suppressor cells; tumor immunology; autoimmunity
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The aberrant activation of Notch receptor signaling in human patients or murine models is implicated in the development of a variety of hematological malignancies, including T-acute lymphoblastic leukemia, B-acute lymphoblastic leukemia, multiple myeloma, Hodgkin lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, mantle cell lymphoma, splenic marginal zone lymphoma and follicular lymphoma. In some of these malignancies, the mechanism of Notch aberrant activity relies on genetic mutations targeting the receptor itself or its negative regulators, such as the ubiquitin ligase FBXW7. In other malignancies, increased activation of the Notch pathway is due to receptor upregulation or increased expression of specific ligands in tumor cells and/or microenvironment cells. Non-mutational, ligand-independent mechanisms involving an aberrant activation of Notch positive regulators or dysregulated vesicle trafficking of Notch receptors and/or ligands might also contribute to sustaining Notch activity in cancer cells. In turn, Notch signaling directs several pathways, mediated by transcriptional factors, kinases, antiapoptotic proteins and cytokines, which further contribute to cancer development and progression, by influencing tumor cell behavior and/or tumor microenvironment cell subsets. These processes generate an amplified signaling network, leading to uncontrolled cell growth and resistance to therapy. Therefore, detailed knowledge of the complex cross-talk among Notch, its upstream regulators and its effectors may lead to advances in better understanding the initiation, progression and outcome of hematologic malignancies, with the final aim to develop new targeted therapeutic strategies.

In this Special Issue, we are collecting original articles and reviews that provide new insights into the role of Notch signaling activation in hematologic malignancies, focusing on Notch’s interaction with other signaling pathways and on the mechanisms by which this cross-talk contributes to hematologic cancer initiation, progression and therapy resistance.

Prof. Dr. Emanuela Rosati
Dr. Antonio F. Campese
Guest Editors

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Keywords

  • Notch
  • Notch signaling activation
  • Notch interacting pathways
  • hematological malignancies
  • tumor microenvironment
  • Notch regulators
  • Notch effectors
  • tumor initiation
  • tumor progression
  • therapy resistance

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Published Papers (5 papers)

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Research

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15 pages, 2976 KiB  
Article
The NF-κB1/p50 Subunit Influences the Notch/IL-6-Driven Expansion of Myeloid-Derived Suppressor Cells in Murine T-Cell Acute Lymphoblastic Leukemia
by Behnaz Abdollahzadeh, Noemi Martina Cantale Aeo, Nike Giordano, Andrea Orlando, Maria Basciani, Giovanna Peruzzi, Paola Grazioli, Isabella Screpanti, Maria Pia Felli and Antonio Francesco Campese
Int. J. Mol. Sci. 2024, 25(18), 9882; https://doi.org/10.3390/ijms25189882 - 13 Sep 2024
Viewed by 946
Abstract
T-cell acute lymphoblastic leukemia is an aggressive neoplasia due to hyper-proliferation of lymphoid progenitors and lacking a definitive cure to date. Notch-activating mutations are the most common in driving disease onset and progression, often in combination with sustained activity of NF-κB. Myeloid-derived suppressor [...] Read more.
T-cell acute lymphoblastic leukemia is an aggressive neoplasia due to hyper-proliferation of lymphoid progenitors and lacking a definitive cure to date. Notch-activating mutations are the most common in driving disease onset and progression, often in combination with sustained activity of NF-κB. Myeloid-derived suppressor cells represent a mixed population of immature progenitors exerting suppression of anti-cancer immune responses in the tumor microenvironment of many malignancies. We recently reported that in a transgenic murine model of Notch3-dependent T-cell acute lymphoblastic leukemia there is an accumulation of myeloid-derived suppressor cells, dependent on both Notch signaling deregulation and IL-6 production inside tumor T-cells. However, possible interaction between NF-κB and Notch in this context remains unexplored. Interestingly, we also reported that Notch3 transgenic and NF-κB1/p50 deleted double mutant mice display massive myeloproliferation. Here, we demonstrated that the absence of the p50 subunit in these mice dramatically enhances the induction and suppressive function of myeloid-derived suppressor cells. This runs in parallel with an impressive increase in IL-6 concentration in the peripheral blood serum, depending on IL-6 hyper-production by tumor T-cells from double mutant mice. Mechanistically, IL-6 increase relies on loss of the negative control exerted by the p50 subunit on the IL-6 promoter. Our results reveal the Notch/NF-κB cross-talk in regulating myeloid-derived suppressor cell biology in T-cell leukemia, highlighting the need to consider carefully the pleiotropic effects of NF-κB-based therapy on the tumor microenvironment. Full article
(This article belongs to the Special Issue The Role of Notch Signaling Activation and Its Cross-Talk with Other Pathways in Hematological Malignancies)
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12 pages, 2334 KiB  
Article
The Potential of JAG Ligands as Therapeutic Targets and Predictive Biomarkers in Multiple Myeloma
by Natalia Platonova, Elisa Lazzari, Michela Colombo, Monica Falleni, Delfina Tosi, Domenica Giannandrea, Valentina Citro, Lavinia Casati, Domenica Ronchetti, Niccolò Bolli, Antonino Neri, Federica Torricelli, Leslie A. Crews, Catriona H. M. Jamieson and Raffaella Chiaramonte
Int. J. Mol. Sci. 2023, 24(19), 14558; https://doi.org/10.3390/ijms241914558 - 26 Sep 2023
Cited by 1 | Viewed by 1451
Abstract
The NOTCH ligands JAG1 and JAG2 have been correlated in vitro with multiple myeloma (MM) cell proliferation, drug resistance, self-renewal and a pathological crosstalk with the tumor microenvironment resulting in angiogenesis and osteoclastogenesis. These findings suggest that a therapeutic approach targeting JAG ligands [...] Read more.
The NOTCH ligands JAG1 and JAG2 have been correlated in vitro with multiple myeloma (MM) cell proliferation, drug resistance, self-renewal and a pathological crosstalk with the tumor microenvironment resulting in angiogenesis and osteoclastogenesis. These findings suggest that a therapeutic approach targeting JAG ligands might be helpful for the care of MM patients and lead us to explore the role of JAG1 and JAG2 in a MM in vivo model and primary patient samples. JAG1 and JAG2 protein expression represents a common feature in MM cell lines; therefore, we assessed their function through JAG1/2 conditional silencing in a MM xenograft model. We observed that JAG1 and JAG2 showed potential as therapeutic targets in MM, as their silencing resulted in a reduction in the tumor burden. Moreover, JAG1 and JAG2 protein expression in MM patients was positively correlated with the presence of MM cells in patients’ bone marrow biopsies. Finally, taking advantage of the Multiple Myeloma Research Foundation (MMRF) CoMMpass global dataset, we showed that JAG2 gene expression level was a predictive biomarker associated with patients’ overall survival and progression-free survival, independently from other main molecular or clinical features. Overall, these results strengthened the rationale for the development of a JAG1/2-tailored approach and the use of JAG2 as a predictive biomarker in MM. Full article
(This article belongs to the Special Issue The Role of Notch Signaling Activation and Its Cross-Talk with Other Pathways in Hematological Malignancies)
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Review

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12 pages, 1041 KiB  
Review
NOTCH Signaling in Mantle Cell Lymphoma: Biological and Clinical Implications
by Leigh Deshotels, Firas M. Safa and Nakhle S. Saba
Int. J. Mol. Sci. 2023, 24(12), 10280; https://doi.org/10.3390/ijms241210280 - 17 Jun 2023
Cited by 5 | Viewed by 2665
Abstract
Despite major progress in mantle cell lymphoma (MCL) therapeutics, MCL remains a deadly disease with a median survival not exceeding four years. No single driver genetic lesion has been described to solely give rise to MCL. The hallmark translocation t(11;14)(q13;q32) requires additional genetic [...] Read more.
Despite major progress in mantle cell lymphoma (MCL) therapeutics, MCL remains a deadly disease with a median survival not exceeding four years. No single driver genetic lesion has been described to solely give rise to MCL. The hallmark translocation t(11;14)(q13;q32) requires additional genetic alterations for the malignant transformation. A short list of recurrently mutated genes including ATM, CCND1, UBR5, TP53, BIRC3, NOTCH1, NOTCH2, and TRAF2 recently emerged as contributors to the pathogenesis of MCL. Notably, NOTCH1 and NOTCH2 were found to be mutated in multiple B cell lymphomas, including 5–10% of MCL, with most of these mutations occurring within the PEST domain of the protein. The NOTCH genes play a critical role in the early and late phases of normal B cell differentiation. In MCL, mutations in the PEST domain stabilize NOTCH proteins, rendering them resistant to degradation, which subsequently results in the upregulation of genes involved in angiogenesis, cell cycle progression, and cell migration and adhesion. At the clinical level, mutated NOTCH genes are associated with aggressive features in MCL, such as the blastoid and pleomorphic variants, a shorter response to treatment, and inferior survival. In this article, we explore in detail the role of NOTCH signaling in MCL biology and the ongoing efforts toward targeted therapeutic interventions. Full article
(This article belongs to the Special Issue The Role of Notch Signaling Activation and Its Cross-Talk with Other Pathways in Hematological Malignancies)
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31 pages, 1695 KiB  
Review
Notch Partners in the Long Journey of T-ALL Pathogenesis
by María Luisa Toribio and Sara González-García
Int. J. Mol. Sci. 2023, 24(2), 1383; https://doi.org/10.3390/ijms24021383 - 10 Jan 2023
Cited by 8 | Viewed by 3044
Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological disease that arises from the oncogenic transformation of developing T cells during T-lymphopoiesis. Although T-ALL prognosis has improved markedly in recent years, relapsing and refractory patients with dismal outcomes still represent a major clinical [...] Read more.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological disease that arises from the oncogenic transformation of developing T cells during T-lymphopoiesis. Although T-ALL prognosis has improved markedly in recent years, relapsing and refractory patients with dismal outcomes still represent a major clinical issue. Consequently, understanding the pathological mechanisms that lead to the appearance of this malignancy and developing novel and more effective targeted therapies is an urgent need. Since the discovery in 2004 that a major proportion of T-ALL patients carry activating mutations that turn NOTCH1 into an oncogene, great efforts have been made to decipher the mechanisms underlying constitutive NOTCH1 activation, with the aim of understanding how NOTCH1 dysregulation converts the physiological NOTCH1-dependent T-cell developmental program into a pathological T-cell transformation process. Several molecular players have so far been shown to cooperate with NOTCH1 in this oncogenic process, and different therapeutic strategies have been developed to specifically target NOTCH1-dependent T-ALLs. Here, we comprehensively analyze the molecular bases of the cross-talk between NOTCH1 and cooperating partners critically involved in the generation and/or maintenance and progression of T-ALL and discuss novel opportunities and therapeutic approaches that current knowledge may open for future treatment of T-ALL patients. Full article
(This article belongs to the Special Issue The Role of Notch Signaling Activation and Its Cross-Talk with Other Pathways in Hematological Malignancies)
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Other

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13 pages, 3362 KiB  
Brief Report
Thymic-Epithelial-Cell-Dependent Microenvironment Influences Proliferation and Apoptosis of Leukemic Cells
by Sandesh Kumar Patel, Nadezda Zhdanovskaya, Ilaria Sergio, Antonella Cardinale, Marco Rosichini, Claudia Varricchio, Eleonora Pace, Carlo Capalbo, Franco Locatelli, Alberto Macone, Enrico Velardi, Rocco Palermo and Maria Pia Felli
Int. J. Mol. Sci. 2024, 25(3), 1412; https://doi.org/10.3390/ijms25031412 - 24 Jan 2024
Viewed by 1829
Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is a hematological cancer characterized by the infiltration of immature T-cells in the bone marrow. Aberrant NOTCH signaling in T-ALL is mainly triggered by activating mutations of NOTCH1 and overexpression of NOTCH3, and rarely is it linked to [...] Read more.
T-cell acute lymphoblastic leukemia (T-ALL) is a hematological cancer characterized by the infiltration of immature T-cells in the bone marrow. Aberrant NOTCH signaling in T-ALL is mainly triggered by activating mutations of NOTCH1 and overexpression of NOTCH3, and rarely is it linked to NOTCH3-activating mutations. Besides the known critical role of NOTCH, the nature of intrathymic microenvironment-dependent mechanisms able to render immature thymocytes, presumably pre-leukemic cells, capable of escaping thymus retention and infiltrating the bone marrow is still unclear. An important challenge is understanding how leukemic cells shape their tumor microenvironment to increase their ability to infiltrate and survive within. Our previous data indicated that hyperactive NOTCH3 affects the CXCL12/CXCR4 system and may interfere with T-cell/stroma interactions within the thymus. This study aims to identify the biological effects of the reciprocal interactions between human leukemic cell lines and thymic epithelial cell (TEC)-derived soluble factors in modulating NOTCH signaling and survival programs of T-ALL cells and TECs. The overarching hypothesis is that this crosstalk can influence the progressive stages of T-cell development driving T-cell leukemia. Thus, we investigated the effect of extracellular space conditioned by T-ALL cell lines (Jurkat, TALL1, and Loucy) and TECs and studied their reciprocal regulation of cell cycle and survival. In support, we also detected metabolic changes as potential drivers of leukemic cell survival. Our studies could shed light on T-cell/stroma crosstalk to human leukemic cells and propose our culture system to test pharmacological treatment for T-ALL. Full article
(This article belongs to the Special Issue The Role of Notch Signaling Activation and Its Cross-Talk with Other Pathways in Hematological Malignancies)
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