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Lymph node biopsy specimens of cHD and ALCL. (A-D) Paraffin- embedded sections immunostained for Notch1 and counterstained with hematoxylin. HRS cells (A, B; arrows) with bilobed or multilobed nuclei, huge inclusionlike nucleoli, and abundant cytoplasm and (C) large pleomorphic cells with prominent nucleoli, ALCL tumor cells, are intensely labeled by anti-Notch1 antibodies. Bystander cells and reactive lymphoid tissue (D) show low to undetectable immunoreactivity levels against Notch1. (E, G) Immunostaining for Jagged1. Jagged1 is expressed in HRS cells (E, arrows) and in tumor cells of ALCL (G). (F) Radioactive in situ hybridization of a case of cHD with probes specific for Jagged1. Endothelial and smooth muscle cells show abundant Jagged1 mRNA expression (arrow). Original magnification ϫ 200 (A-C), ϫ 100 (D), ϫ 200 (E-G).
Source publication
Notch signaling controls cell fate decisions of hematopoietic progenitors by inhibiting certain steps of differentiation and inducing either self-renewal or differentiation toward lymphoid or myeloid lineages. In addition, truncated Notch1 alleles could be associated with 10% of all cases of human T lymphoblastic leukemia and, when introduced into...
Citations
... For example, CCL17, also known as blood thymus and activation-regulated chemokine (TARC) has proven to be a useful diagnostic biomarker in children with classical Hodgkin lymphoma. 9, 10 It has never been studied whether CCL17 can serve as a biomarker in non-Hodgkin lymphoma and T-LBL in particular. CCL17 is constitutively produced in the thymus, acting as a powerful T-cell chemoattractant. ...
... In classical Hodgkin lymphoma patients, CCL17 production can be induced by NOTCH1 and CCL17 is highly expressed by the Reed-Sternberg cells, thereby creating a specific supporting tumor microenvironment that recruits T-cells. 10 Considering the importance of NOTCH1 and strong preference of malignant T-cells in T-LBL for the thymus, we hypothesize that CCL17 is of importance in the pathophysiology of T-LBL and creating a thymic microenvironment that favors the T-LBL cells. ...
Twenty percent of children with T‐cell lymphoblastic lymphoma (T‐LBL) will relapse and have an extremely poor outcome. Currently, we can identify a genetically low‐risk subgroup in pediatric T‐LBL, yet these high‐risk patients who need intensified or alternative treatment options remain undetected. Therefore, there is an urgent need to recognize these high‐risk T‐LBL patients through identification of molecular characteristics and biomarkers. By using RNA sequencing which was performed in 29/49 T‐LBL patients who were diagnosed in the Princess Maxima Center for Pediatric Oncology between 2018 and 2023, we discovered a previously unknown high‐risk biological subgroup of children with T‐LBL. This subgroup is characterized by NOTCH1 gene fusions, found in 21% of our T‐LBL cohort (6/29). All patients presented with a large mediastinal mass, pleural/pericardial effusions, and absence of blasts in the bone marrow, blood, and central nervous system. Blood CCL17 (C‐C Motif Chemokine Ligand 17, TARC) levels were measured at diagnosis in 26/29 patients, and all six patients with NOTCH1 gene fusions patients exclusively expressed highly elevated blood CCL17 levels, defining a novel and previously not known clinically relevant biomarker for T‐cell lymphoblastic lymphoma. Four out of these six patients relapsed during therapy, a fifth developed a therapy‐related acute myeloid leukemia during maintenance therapy. These data indicate that T‐LBL patients with a NOTCH1 fusion have a high risk of relapse which can be easily identified using a blood CCL17 screening at diagnosis. Further molecular characterization through NOTCH1 gene fusion analysis offers these patients the opportunity for treatment intensification or new treatment strategies.
... NOTCH1 is highly expressed in cHL, whereas its ligand Jagged1 (JAG1) is present on infiltrating cells. Their interaction supports the proliferation of HRS cells [128]. NOTCH1 is regulated by miR-363-3p in gastric cancer [111]. ...
Simple Summary
We explored how small non-coding RNAs, known as miRNAs, are involved in the pathogenesis of cHL, a lymphoma originating from B cells. While miRNAs have shown broad effects in normal cellular processes and cancers, their contribution to cHL has been less explored. We organized the published human miRNA profiling studies of cHL and selected genes that are crucial for cHL pathogenesis such as those leading to the loss of B-cell phenotypes, immune evasion, and promotion of tumor growth. By providing a detailed analysis of the interactions between these miRNAs and their target genes, our review not only enhances the understanding of cHL molecular mechanisms but also paves the way for further research into how specific miRNAs could be involved in cHL progression.
Abstract
Classical Hodgkin lymphoma (cHL) is a hematological malignancy of B-cell origin. The tumor cells in cHL are referred to as Hodgkin and Reed–Sternberg (HRS) cells. This review provides an overview of the currently known miRNA–target gene interactions. In addition, we pinpointed other potential regulatory roles of microRNAs (miRNAs) by focusing on genes related to processes relevant for cHL pathogenesis, i.e., loss of B-cell phenotypes, immune evasion, and growth support. A cHL-specific miRNA signature was generated based on the available profiling studies. The interactions relevant for cHL were extracted by comprehensively reviewing the existing studies on validated miRNA–target gene interactions. The miRNAs with potential critical roles included miR-155-5p, miR-148a-3p, miR-181a-5p, miR-200, miR-23a-3p, miR-125a/b, miR-130a-3p, miR-138, and miR-143-3p, which target, amongst others, PU.1, ETS1, HLA-I, PD-L1, and NF-κB component genes. Overall, we provide a comprehensive perspective on the relevant miRNA–target gene interactions which can also serve as a foundation for future functional studies into the specific roles of the selected miRNAs in cHL pathogenesis.
... Since constitutive activity of NF-kB and Notch pathways is a hallmark of HRS cells [20][21][22][23] and, as mentioned above, Stanelle et al. have linked GATA3 expression in HRS cells to the constitutive activity of NF-kB and Notch pathways, the GATA3 negativity in a sizeable portion of cHL cases requires further studies to be explained [12][13][14][15]. It could be hypothesized that GATA3 downregulated expression in HRS cells in a subset of cHL results from reduced NF-kB and/or Notch activity. ...
GATA3 is a transcription factor involved in T-cell maturation and has been previously shown to be aberrantly overexpressed in malignant Hodgkin and Reed–Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL). However, the immunophenotypes of the cell types expressing GATA3 have not been precisely characterized so far in cHL tissues. In this single-center retrospective cohort study we analyzed the expression patterns of GATA3 alone and in combination with B, T, NK or macrophage-associated markers in 73 cases with newly diagnosed cHL and investigated for a possible correlation with clinical and laboratory parameters. Immunohistochemistry (single and double) was performed using GATA3 alone and in combination with CD20, CD3, CD56, CD68, CD30 or CD15. Clinical and laboratory parameters were collected and correlated with the expression of GATA 3. GATA3 nuclear expression was found in HRS cells in 39/73 (54%) cases of cHL. The Nodular Sclerosis (NS) subtype showed the highest positivity rate (35/56, 63%), followed by mixed cellularity (MC; 4/14, 29%) and lymphocyte rich (LR; 0/3). Double immunostainings showed that GATA3 was expressed by CD30+ or CD15+ HRS cells and a few CD3+ T-cells, whereas GATA3 expression was not detected in CD20, CD56 or CD68+ cells. GATA3-negative cHL was significantly associated with unfavorable prognostic factors such as older age at diagnosis and increased levels of serum β2-microglobulin. The heterogenous expression patterns of GATA3 in HRS cells that were observed in a substantial proportion of cHL, mainly in the NS subtype, further support the biological heterogeneity of cHL.
... In cHL, NOTCH1 expression in HRS cells promotes cell proliferation by interacting with its ligand JAGGED1 [12]. Interestingly, JAGGED1 has been demonstrated to be expressed both by HRS cells themselves and cells resident in the tumoral microenvironment, such as epithelioid cells neighboring HRS cells [50]. ...
Classic Hodgkin lymphoma (cHL) constitutes a B-cell neoplasm derived from germinal center lymphocytes. Despite high cure rates (80–90%) obtained with the current multiagent protocols, a significant proportion of cHL patients experience recurrences, characterized by a lower sensitivity to second-line treatments. The genomic background of chemorefractory cHL is still poorly understood, limiting personalized treatment strategies based on molecular features. In this study, using a targeted next-generation sequencing (NGS) panel specifically designed for cHL research, we compared chemosensitive and chemorefractory diagnostic tissue samples of cHL patients. Furthermore, we longitudinally examined paired diagnosis–relapsesamples of chemorefractory cHL in order to define patterns of dynamic evolution and clonal selection. Pathogenic variants in NOTCH1 and NOTCH2 genes frequently arise in cHL. Mutations in genes associated with epigenetic regulation (CREBBP and EP300) are particularly frequent in relapsed/refractory cHL. The appearance of novel clones characterized by mutations previously not identified at diagnosis is a common feature in cHL cases showing chemoresistance to frontline treatments. Our results expand current molecular and pathogenic knowledge of cHL and support the performance of molecular studies in cHL prior to the initiation of first-line therapies.
... Despite differences in gene alterations between ALK + ALCL and ALK -ALCL, they share some deregulated transcription factors programs like STAT3 and NOTCH1 activation, IRF4, and c-MYC overexpression (9,(26)(27)(28)(29). STAT3 activation has been reported in ALK + ALCL and ALK -ALCL as a well-defined oncogenic driver through different machanisms (9,(12)(13)(14)(29)(30)(31). ...
Aims
The differential diagnosis between ALK-negative anaplastic large cell lymphoma (ALK⁻ ALCL) and peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) with high expression of CD30 (CD30high) are essential. However, no reliable biomarker is available in daily practice except CD30. STAT3 is characteristically activated in ALCL. We aimed to investigate whether the status of STAT3 phosphorylation could help the differential diagnosis.
Methods
The status of phosphorylation of STAT3 was examined using two antibodies against pSTAT3-Y705 and pSTAT3-S727 by immunohistochemistry in ALK⁺ ALCL (n=33), ALK⁻ ALCL (n=22) and PTCL, NOS (n=34). Ten PTCL, NOS with diffuse CD30 expression were defined as CD30high PTCL, NOS. Flowcytometric analysis were performed to evaluate the expression of pSTAT3-Y705/S727 in PTCL, NOS (n=3).
Results
The median H-scores of pSTAT3-Y705 and S727 were 280 and 260 in ALK⁺ ALCL, 250 and 240 in ALK⁻ ALCL, and 45 and 75 in CD30high subgroup, respectively. Using H score of 145 as the cutoff value, pSTAT3-S727 alone distinguished between ALK⁻ ALCL and CD30high PTCL, NOS with a sensitivity of 100% and specificity of 83%. Additionally, pSTAT3-S727, but not pSTAT3-Y705, was also expressed by background tumor-infiltrating lymphocytes (S727TILs) in PTCL, NOS. PTCL, NOS patients with high S727TILs H score had a favorable prognosis than those with no TILs (3-year OS rate: 43% vs. 0, p=0.013) or low S727TILs (3-year OS rate: 43% vs. 0, p=0.099). Flowcytometric analysis revealed that of the three patients investigated, two had enhanced pSTAT-S727 signals in neoplastic cell populations, and all three patients were negative for pSTAT3-Y705 expression in both tumor cells and background lymphocytes.
Conclusions
pSTAT3-Y705/S727 can be used to help distinguish ALK⁻ ALCL from CD30high PTCL, NOS and pSTAT3-S727 expression by TILs predicts the prognosis of a subset of PTCL, NOS.
... 64 Contradictorily, Notch1 is highly expressed in some B-cell and T-cell derived tumors of Hodgkin lymphoma and anaplastic large-cell lymphoma. 65 Aberrant expression of Notch1 is also associated with abnormal proliferation and survival of various lymphomas, 66 altogether depicting the dual role of the Notch pathway in a particular tumor subtype; the underlying reason for this is still undetermined. ...
The Notch pathway is remarkably simple without the interventions of secondary messengers. It possesses a unique receptor-ligand interaction that imparts signaling upon cleavage of the receptor followed by the nuclear localization of its cleaved intracellular domain. It is found that the transcriptional regulator of the Notch pathway lies at the intersection of multiple signaling pathways that enhance the aggressiveness of cancer. The preclinical and clinical evidence supports the pro-oncogenic function of Notch signaling in various tumor subtypes. Owing to its oncogenic role, the Notch signaling pathway assists in enhanced tumorigenesis by facilitating angiogenesis, drug resistance, epithelial to mesenchymal transition, etc., which is also attributed to the poor outcome in patients. Therefore, it is extremely vital to discover a suitable inhibitor to downregulate the signal-transducing ability of Notch. The Notch inhibitory agents, such as receptor decoys, protease (ADAM and γ-secretase) inhibitors, and monoclonal/bispecific antibodies, are being investigated as candidate therapeutic agents. Studies conducted by our group exemplify the promising results in ablating tumorigenic aggressiveness by inhibiting the constituents of the Notch pathway. This review deals with the detailed mechanism of the Notch pathways and their implications in various malignancies. It also bestows us with the recent therapeutic advances concerning Notch signaling in the context of monotherapy and combination therapy.
... 56 In cHL cell lines, NOTCH1 signaling promotes HRS cell survival and proliferation. 57,58 Evidence from gene expression profiling indicates that the composition of the TME varies depending on the Epstein Barr virus tumor status. 59 Moreover, sequencing and gene expression studies in HRS cells suggest that the genotype and phenotype of HRS cells strongly influence cellular cross talk within the TME. ...
Classic Hodgkin lymphoma (cHL) is characterized by a tumor microenvironment (TME) containing inflammatory/immune cells. Follicular lymphoma, mediastinal grey zone lymphoma and diffuse large B-cell lymphomas, may show a TME containing inflammatory/immune cells, but the TMEs are quite different. In these B-cell lymphomas and cHL, PD-1/PD-L1 blockade drugs differ in their effectiveness in patients with refractory/relapsed disease. Research should still explore innovative assays that could reveal which molecules are influencing the sensitivity or the resistance to therapy in an individual patient.
... Regarding its effect on autophagy process, Doxo resulted in an increase in LC3 positive cells to 78.8% and presence of autophagosomes. These observations are in accordance with previous studies suggested the pro-autophagic effect of Doxo through induction of cytoprotective autophagic ux which diminishes the cytotoxic effects of Doxo (34,35). Thus, may explain the observed proliferative activities of either Doxo or CNC10 through increasing cell cycle arrest at S phase and decreasing in G0/1 cell arrest. ...
TNBC is a subtype of breast cancer which is characterized by its aggressiveness, poor survival and short overall survival. Notch signaling pathway has received great attention as one of the most important potential targets for developing a novel therapeutic strategy.
Purpose, the present study is an attempt to assess the promising chemotherapeutic activities of copper (I) nicotinate (CNC) through its impact on the expression of downstream genes of Notch1 signaling pathway and the cell fate of TNBC. The co-treatment of TNBC cells with doxorubicin (Doxo) and CNC was also investigated.
Methods, to approach the objective of the present study, triple negative breast cancer HCC1806 and MDA MB 231 cell line were utilized. Cell viability assay, MTT assay, was used to determine IC50 values of CNC and Doxo. After treatment, cell cycle distribution and indirect antibody labeling of microtubule-associated protein light chain 3 (LC3) were determined by flow cytometry. Real time PCR was used to detect the changes in gene expressions that are involved Notch1 signaling pathway. Moreover, autophagosomes were monitored and imaged by TEM.
Results, treatment of TNBC cells with CNC modulated Notch1 signaling pathways in different manners with respect to the type of cells and the applied dose of CNC.
Conclusion, the observed pro-apoptotic of CNC in addition to its pro- or anti- autophagic activities may reflect the possible anti-cancer activities of CNC in both types of TNBC. However, cell type and CNC dose should be considered.
... The W390A mutation in MLV IN significantly retargeted viral integration away from enhancers toward oncogenes bodies such as Notch1 and Ppp1r16b. Notch1 has been widely described as one of the driver genes in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) (88)(89)(90), while Ppp1r16b can promote aggressive lymphomas in mice (91). The truncation of Notch1 can generate lymphomas by the loss of the PEST domain located in the 39 end of the Notch1 gene, which leads to an enhanced protein half-life and, therefore, longer activity as a transcription factor in the nucleus (92). ...
In this study, we have shown that the in vivo replication of murine leukemia virus happens independently of BET proteins, which are key host determinants involved in retroviral integration site selection. This finding opens a new research line in the discovery of alternative viral or host factors that may complement the dominant host factor.
... Continuous activation of NF-kB is necessary to maintain the proliferation and survival of Hodgkin tumor cells. It has been shown that Notch1 and its ligand Jagged1 are strongly expressed in HRS cells, with pathway activation accelerating tumor cell growth and inhibiting therapies-induced apoptosis (Jundt et al., 2002). Interestingly, the specific crosstalk between NF-kB and Notch1 was recently highlighted with pharmacological Notch inhibition leading to a dose-dependent reduction in NF-kB transcriptional activity (Schwarzer et al., 2012). ...
The Notch signaling pathway is evolutionarily conserved across all metazoans and contributes to the development and maintenance of numerous tissues. Consequently, many diseases result from aberrant Notch signaling including cancer. This article will overview the current understanding of Notch deregulation in both hematological malignancies and solid tumors. It is interesting to note that the Notch pathway plays controversial roles during neoplastic transformation, which is highly dependent on biological context as well as tumorigenic stage. For example, Notch signaling has emerged as a major regulator contributing to T-cell acute lymphoblastic leukemia (T-ALL); on contrast functions as a tumor suppressor in squamous cell carcinomas, a type of skin cancer. Based on in-depth mechanistic insights on the tumor-promoting role of Notch, therapeutic targeting of Notch has emerged as a promising anti-tumor strategy for clinical development. These reagents either obstruct Notch receptor cleavages such as γ-secretase inhibitors (GSIs) or interfere with the Notch ligand-receptor interaction by monoclonal antibodies (mAbs). GSIs and mAbs administered as single agent in early phases of clinical trials have shown short-lived anti-tumor activity, and these agents face challenges including lack of durable efficacy and development of drug resistance. Biomarkers of efficacy or combination strategy should be of importance for a successful development of anti-Notch therapies.
