Щоб переглянути інші типи публікацій з цієї теми, перейдіть за посиланням: Notch signaling, Leukemia, Chemosensitivity.
Статті в журналах з теми "Notch signaling, Leukemia, Chemosensitivity"
Оформте джерело за APA, MLA, Chicago, Harvard та іншими стилями
Ознайомтеся з топ-50 статей у журналах для дослідження на тему "Notch signaling, Leukemia, Chemosensitivity".
Біля кожної праці в переліку літератури доступна кнопка «Додати до бібліографії». Скористайтеся нею – і ми автоматично оформимо бібліографічне посилання на обрану працю в потрібному вам стилі цитування: APA, MLA, «Гарвард», «Чикаго», «Ванкувер» тощо.
Також ви можете завантажити повний текст наукової публікації у форматі «.pdf» та прочитати онлайн анотацію до роботи, якщо відповідні параметри наявні в метаданих.
Переглядайте статті в журналах для різних дисциплін та оформлюйте правильно вашу бібліографію.
1
Láinez-González, Daniel, Juana Serrano-López, and Juan Manuel Alonso-Dominguez. "Understanding the Notch Signaling Pathway in Acute Myeloid Leukemia Stem Cells: From Hematopoiesis to Neoplasia." Cancers 14, no. 6 (March 12, 2022): 1459. http://dx.doi.org/10.3390/cancers14061459.
Повний текст джерелаАнотація:
The Notch signaling pathway is fundamental to early fetal development, but its role in acute myeloid leukemia is still unclear. It is important to elucidate the function that contains Notch, not only in acute myeloid leukemia, but in leukemic stem cells (LSCs). LSCs seem to be the principal cause of patient relapse. This population is in a quiescent state. Signaling pathways that govern this process must be understood to increase the chemosensitivity of this compartment. In this review, we focus on the conserved Notch signaling pathway, and its repercussions in hematopoiesis and hematological neoplasia. We found in the literature both visions regarding Notch activity in acute myeloid leukemia. On one hand, the activation of Notch leads to cell proliferation, on the other hand, the activation of Notch leads to cell cycle arrest. This dilemma requires further experiments to be answered, in order to understand the role of Notch not only in acute myeloid leukemia, but especially in LSCs.
2
Takam Kamga, Paul, Giada Dal Collo, Martina Midolo, Annalisa Adamo, Pietro Delfino, Angela Mercuri, Simone Cesaro, et al. "Inhibition of Notch Signaling Enhances Chemosensitivity in B-cell Precursor Acute Lymphoblastic Leukemia." Cancer Research 79, no. 3 (December 18, 2018): 639–49. http://dx.doi.org/10.1158/0008-5472.can-18-1617.
Повний текст джерела
3
Takam Kamga, Paul, Bassi Giulio, Adriana Cassaro, Roberta Stradoni, Martina Midolo, Omar Perbellini, and Mauro Krampera. "Role of Stromal Cell-Mediated Notch Signaling in AML Resistance to Chemotherapy." Blood 124, no. 21 (December 6, 2014): 1044. http://dx.doi.org/10.1182/blood.v124.21.1044.1044.
Повний текст джерелаАнотація:
Abstract Introduction: Our group has recently shown that bone marrow-mesenchymal stromal cell (BM-MSCs)-mediated Notch signaling may control survival and chemoresistance of B-acute lymphoblastic leukemia (B-ALL) and chronic lymphocytic leukemia (CLL) cells. Conversely, the role of Notch signaling in acute myeloid leukemia (AML) remains controversial, as its contribution to the crosstalk between BM-MSCs and AML cells is still unknown. Thus, we evaluated the role of the Notch pathway in the proliferation, survival and chemoresistance of AML primary blast cells in co-culture with BM-MSCs. Methods: AML blast cells were obtained after informed consent from bone marrow samples (30) and peripheral blood (20) of AML patients, according to the Institutional guidelines. BM-MSCs were expanded from bone marrow of 12 healthy donors (BM-MSCs) and of 12 AML-patients (BM-MSCs*). PCR, FACS analysis and western immunoblotting were used to study the expression of Notch receptors and ligands, as well as Notch activation status, in AML cells and BM-MSCs. AML cells were co-cultured with BM-MSCs or BM-MSCs* at 10:1 (AML:BM-MSCs) ratio for 2 to 3 days in presence of Cytarabine, Etoposide, Idarubicin, as well as in presence or absence of anti-Notch-1, -2, -3, -4, anti-Jagged1, -2 and anti-DLL3 blocking antibodies or gamma secretase inhibitor-XII (GSI-XII). Cell viability was evaluated by Annexin-V/Propidium Iodide (PI) and MTT; proliferation and cell cycle were assessed through CFSE dilution and PI methods, respectively. Results: AML cells expressed Notch receptors and ligands, showing Notch-1, -2, Jagged-1, -2 and DLL-3 signature, while BM-MSCs/ BM-MSCs* showed expression of Notch-1, -2, -3, -4 and Jagged-1, -2 and DLL-1. We then analyzed Notch activation in different cell types by evaluating the expression of NICD-1, -2, -3 as well as Hes-1. We found that at least 50% of AML samples showed basal Notch activation while BM-MSCs/ BM-MSCs* showed slight Notch activation. The expression and activation pattern were modulated after 3 days of co-culture with either BM-MSCs or BM-MSCs*. The pan blockade of Notch signaling by GSI-XII were capable to inhibit AML cell proliferation as well as induce AML cell apoptosis in culture or in co-culture with BM-MSCs/ BM-MSCs*. The addition of chemotherapeutic agents decreased AML cell viability in culture, while a significant rescue from apoptosis was observed when cocultured with BM-MSCs or BM-MSCs*. Pan Notch signaling blockade by either GSI-XII or combination of Notch receptor-blocking antibodies in presence of chemotherapeutic agents significantly lowered the supportive role of BM-MSCs towards AML cell lines. The specific blockade of Notch-1, -2, -3 or Jagged-1, -2 rescued partially the chemosensibility, while blockade of Notch-4 or DLL-3 rescued totally the chemosensitivity of primary AML cells in co-culture with BM-MSCs. Conclusions: These results suggest that Notch signaling may represent a potential therapeutic strategy to overcome bone marrow stromal-mediated survival and chemoresistance of AML. Moreover Notch blocking antibodies were able to impair the survival benefit imparted by bone marrow stromal cells. Therefore blocking Notch antibodies could be a useful strategy to improve the efficiency of AML chemotherapy. Disclosures No relevant conflicts of interest to declare.
4
Nishimura, Akira, Kazuaki Yokoyama, Chika Yamagishi, Takuya Naruto, Tomohiro Morio, Akinori Kanai, Hirotaka Matsui, et al. "Clinical Feature and Genetic Alterations in Myeloid/Natural Killer (NK) Cell Precursor Acute Leukemia and Myeloid/NK Cell Acute Leukemia." Blood 132, Supplement 1 (November 29, 2018): 2824. http://dx.doi.org/10.1182/blood-2018-99-118627.
Повний текст джерелаАнотація:
Abstract Introduction: Myeloid/Natural killer cell precursor acute leukemia (MNKPL) and myeloid/NK cell acute leukemia (MNKL) is a rare hematologic malignancy prevalent in East Asia. MNKPL is characterized by marked extramedullary involvement, immature lymphoblastoid morphology without myeloperoxidase (MPO) reactivity, a CD7+/CD33+/CD34+/CD16−/CD15−/+/HLA-DR+ phenotype, myeloid chemosensitivity, and a poor prognosis. By contrast, MNKL shows no extramedullary involvement, a HLA‐DR−/CD33+/CD16−/CD34−/+ phenotype, myeloid chemosensitivity, and a good prognosis. However, analysis of outcome and genetic alterations in these leukemias are limited. Here, we report outcome and genetic alterations in the patients with MNKPL and MNKL. Methods: The Leukemia and Lymphoma Committee of the Japanese Society of Pediatric Hematology and Oncology (JSPHO) sent out two questionnaires to 110 JSPHO affiliated hospitals. The first questionnaire requested details of the number of pediatric patients with MNKPL or MNKL had been diagnosed during the period 2000-2013. The second questionnaire requested more detailed information about clinical curses. Overall survival (OS) and event free survival (EFS) defined as relapse or death was analyzed. The protocol of this retrospective study was approved by the review boards of JSPHO and Ehime Prefectural Central Hospital. We also performed whole exome sequence (WES) using 7 children's samples (5 MNKPL, 2 MNKL) and target sequence using 2 adult's samples (2 MNKPL) from this and another independent cohort. The research protocol was approved by the review board of TMDU. Results: Thirteen children with MNKPL and 6 children with MNKL were identified. Median age of MNKPL was 8 year-old (range; 0.5-17) and median age of MNKL was 10 year-old (range; 2-13). There are 8 males and 5 females in MNKPL and 4 males and 2 females in MNKL. In MNKPL, central nervous system, mediastinum and lymph node involvement was observed in 1 case respectively. Nasal sinus involvement was observed in 1 case in MNKL. Eleven patients with MNKPL and 3 patients with MNKL were treated with acute myeloid leukemia style chemotherapy and 1 MNKPL patients and 3 MNKL patients were treated with acute lymphoblastic leukemia/non-Hodgkin lymphoma style chemotherapy. Complete remission after induction therapy was achieved in 8/13 MNKPL children and 4/6 MNKL children. Twelve out of 13 MNKPL children and all 6 MNKL children underwent hematopoietic cell transplantation (HCT) with myeloablative conditioning regimen. Median follow up period was 5.3 years in MNKPL and 3.8 years in MNKL patients. 5-year OS of MNKPL and MNKL was 67.3 % and 41.7 %, 5-year EFS of MNKPL and MNKL was 52.7 % and 41.7 % respectively. In genetic analysis, average 148 somatic mutations in MNKPL and 88 somatic mutations in MNKL were identified by WES. In combined analysis using adult cases, the recurrent mutations were observed in NOTCH1, NRAS (n=3, respectively), MAML2, MAP3K1, SIRPA (n=2, respectively) as activating signal genes, and CLTCL1 (n=2) as cell adhesion molecules, and RECQL4 (n=2) as cell cycle/DNA repair molecules, and PRDM2, CREBBP, SETBP1 (n=2, respectively) as epigenetic modifiers, and WT1, ZNF384, BCLAF1 (n=2, respectively) as transcription factors. Conclusions: Previously, it has been reported that outcome of MNKL is relatively good than MNKPL. MNKPL and MNKL children had a poor prognosis in our cohort even though most patients received HCT. We identified alteration of molecules involved in NOTCH signaling and RAS-MAPK pathways. In addition, mutations of several transcription factors such as WT1 were identified. The drugs targeting RAS pathway and epigenetic factors may have the potential to improve outcome. An international collaboration for clinical and cytogenetic research of MNKPL and MNKL is needed as they are complex and rare diseases. Disclosures No relevant conflicts of interest to declare.
5
Guerrero, Carmina Louise Hugo, Yoshiko Yamashita, Megumi Kuba-Miyara, Naoki Imaizumi, Shugo Sakihama, Masaki Hayashi, Takashi Miyagi, et al. "Proteomic Profiling of HTLV-1 Carriers and ATL Patients Reveal TNFR2 As a Novel Diagnostic and Chemosensitivity Biomarker for ATL." Blood 134, Supplement_1 (November 13, 2019): 660. http://dx.doi.org/10.1182/blood-2019-129817.
Повний текст джерелаАнотація:
Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy associated with the human T-cell leukemia virus type I (HTLV-1). Classification of ATL into clinical subtypes acute, lymphoma, chronic and smoldering types was proposed based on prognostic factors, clinical features and natural history of the disease. Although HTLV-1 infection alone is not sufficient to cause ATL and only about 5% of HTLV-1 carriers progress to ATL, the prognosis is generally poor especially for patients with aggressive ATL (i.e., acute, lymphoma or unfavorable chronic types), with a median survival time at around 1 year, even after chemotherapy. Currently, biomarkers to predict ATL onset and progression are limited, making early diagnosis and treatment for ATL challenging. To develop early diagnostic biomarkers for ATL, we performed, for the first time, an extensive proteomic profiling of HTLV-1 carriers and ATL patients as a foundation for establishing a blood-based biomarker panel for ATL. Expression levels of 1305 plasma proteins in HTLV-1 carriers (n=40), untreated ATL patients (n=40, 28 acute; 4 lymphoma; 5 chronic; 3 smoldering), and remission status (n=5) were measured by SOMAscan assay (SomaLogic Inc, Boulder, CO). ATL diagnosis was based on criteria proposed by the Japan Clinical Oncology Group (JCOG) and identification of monoclonal integration of HTLV-1 proviral DNA using Southern blot hybridization method. Deregulated proteins in HTLV-1 versus ATL versus remission states were ranked by significance (Welch's t-test) and discrimination capacity (area under the curve [AUC]). In addition, machine learning algorithms were used to set discrimination boundaries for HTLV-1, ATL, and remission states using some of the top deregulated proteins. Statistical analyses were performed using Python 3.6.2 software. To elucidate on ATL pathogenesis, we further analyzed our proteomic data using Gene Set Enrichment Analysis (GSEA 3.0 hallmarks, curated gene sets) and Gene Ontology (GO Panther Pathways) and determined pathway deregulation among disease states as well as among ATL subtypes. Overrepresented pathways in ATL versus HTLV-1 included inflammation mediated by cytokine and chemokine signaling, angiogenesis, notch signaling, and IL6/JAK/STAT3, among others. Among a total of 176 proteins which were categorized as extremely significant (p<0.00001) with AUC scores ranging from 0.90-0.99, we further confirmed plasma protein concentrations of CD223 (LAG3) (n=40, 2 healthy individuals; 8 HTLV-1 carriers; 10 acute; 8 lymphoma; 6 chronic; 6 smoldering), CD30 (TNFRSF8), TIM-3 (HAVCR2) (n=40, 2 healthy individuals; 8 HTLV-1 carriers; 12 acute; 6 lymphoma, 6 chronic; 6 smoldering), and TNFR2 (TNFRSF1B) (n=79, 5 healthy individuals; 16 HTLV-1 carriers; 26 acute; 9 lymphoma; 11 chronic; 9 smoldering), through ELISA. We discovered significantly higher CD30 and TIM-3 levels in acute ATL versus HTLV-1 carriers (p<0.05) and remarkably high TNFR2 levels among aggressive ATL patients, acute (p<0.001) and lymphoma types (p<0.01) versus HTLV-1 carriers. In addition, a significant decrease in TNFR2 levels among ATL patients who have achieved remission was also seen (p<0.001). These results indicate the potential value of TNFR2 not only as a diagnostic biomarker for ATL, but also for predicting response or failure to therapy. Furthermore, this study represents a novel proteomic approach in developing candidate biomarkers for ATL, by combining data from high-throughput SOMAmer technology, machine learning, proteomic pathway analysis, in addition to previously well-established techniques such as ELISA. Further investigation of TNFR2 and other potential biomarkers in this study need to be done in the near future. Disclosures Fukushima: Daiichi-Sankyo: Research Funding.
6
Aster, Jon C., Warren S. Pear, and Stephen C. Blacklow. "Notch Signaling in Leukemia." Annual Review of Pathology: Mechanisms of Disease 3, no. 1 (February 2008): 587–613. http://dx.doi.org/10.1146/annurev.pathmechdis.3.121806.154300.
Повний текст джерела
7
Aster, Jon C., and Warren S. Pear. "Notch signaling in leukemia." Current Opinion in Hematology 8, no. 4 (July 2001): 237–44. http://dx.doi.org/10.1097/00062752-200107000-00010.
Повний текст джерела
8
Grieselhuber, N. R., J. M. Klco, A. M. Verdoni, T. Lamprecht, S. M. Sarkaria, L. D. Wartman, and T. J. Ley. "Notch signaling in acute promyelocytic leukemia." Leukemia 27, no. 7 (March 4, 2013): 1548–57. http://dx.doi.org/10.1038/leu.2013.68.
Повний текст джерела
9
Lobry, Camille, Panagiotis Ntziachristos, Delphine Ndiaye-Lobry, Philmo Oh, Luisa Cimmino, Nan Zhu, Elisa Araldi, et al. "Notch pathway activation targets AML-initiating cell homeostasis and differentiation." Journal of Experimental Medicine 210, no. 2 (January 28, 2013): 301–19. http://dx.doi.org/10.1084/jem.20121484.
Повний текст джерелаАнотація:
Notch signaling pathway activation is known to contribute to the pathogenesis of a spectrum of human malignancies, including T cell leukemia. However, recent studies have implicated the Notch pathway as a tumor suppressor in myeloproliferative neoplasms and several solid tumors. Here we report a novel tumor suppressor role for Notch signaling in acute myeloid leukemia (AML) and demonstrate that Notch pathway activation could represent a therapeutic strategy in this disease. We show that Notch signaling is silenced in human AML samples, as well as in AML-initiating cells in an animal model of the disease. In vivo activation of Notch signaling using genetic Notch gain of function models or in vitro using synthetic Notch ligand induces rapid cell cycle arrest, differentiation, and apoptosis of AML-initiating cells. Moreover, we demonstrate that Notch inactivation cooperates in vivo with loss of the myeloid tumor suppressor Tet2 to induce AML-like disease. These data demonstrate a novel tumor suppressor role for Notch signaling in AML and elucidate the potential therapeutic use of Notch receptor agonists in the treatment of this devastating leukemia.
10
Kamdje, Armel Hervé Nwabo, and Mauro Krampera. "Notch signaling in acute lymphoblastic leukemia: any role for stromal microenvironment?" Blood 118, no. 25 (December 15, 2011): 6506–14. http://dx.doi.org/10.1182/blood-2011-08-376061.
Повний текст джерелаАнотація:
Abstract Notch signaling pathway regulates many different events of embryonic and adult development; among them, Notch plays an essential role in the onset of hematopoietic stem cells and influences multiple maturation steps of developing lymphoid and myeloid cells. Deregulation of Notch signaling determines several human disorders, including cancer. In the last decade it became evident that Notch signaling plays pivotal roles in the onset and development of T- and B-cell acute lymphoblastic leukemia by regulating the intracellular molecular pathways involved in leukemia cell survival and proliferation. On the other hand, bone marrow stromal cells are equally necessary for leukemia cell survival by preventing blast cell apoptosis and favoring their reciprocal interactions and cross-talk with bone marrow microenvironment. Quite surprisingly, the link between Notch signaling pathway and bone marrow stromal cells in acute lymphoblastic leukemia has been pointed out only recently. In fact, bone marrow stromal cells express Notch receptors and ligands, through which they can interact with and influence normal and leukemia T- and B-cell survival. Here, the data concerning the development of T- and B-cell acute lymphoblastic leukemia has been critically reviewed in light of the most recent findings on Notch signaling in stromal microenvironment.
11
Roti, Giovanni, Claudia Sorrentino, and Antonio Cuneo. "THERAPEUTIC TARGETING OF NOTCH SIGNALING PATHWAY IN HEMATOLOGICAL MALIGNANCIES." Mediterranean Journal of Hematology and Infectious Diseases 11, no. 1 (June 25, 2019): e2019037. http://dx.doi.org/10.4084/mjhid.2019.037.
Повний текст джерелаАнотація:
The Notch pathway plays a key role in several processes including stem-cell self-renewal, proliferation, and cell differentiation. Several studies identified recurrent mutations in hematological malignancies making Notch one of the most desirable target in leukemia and lymphoma. The Notch signaling mediates resistance to therapy and controls cancer stem cells supporting the development of on-target therapeutic strategies to improve patients’ outcome. In this brief review, we outline the therapeutic potential of targeting Notch pathway in T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia and mantle cell lymphoma.
12
Medyouf, Hind, Samuel Gusscott, Carol Wai, Marcus Leung, Florence Armstrong, Francoise Pflumio, Michael Pollak, and Andrew P. Weng. "IGF Signaling Is Critical for Growth and Survival of T-Cell Acute Lymphoblastic Leukemia Cells and Is Potentiated by Notch Upregulation of IGF1R." Blood 112, no. 11 (November 16, 2008): 3811. http://dx.doi.org/10.1182/blood.v112.11.3811.3811.
Повний текст джерелаАнотація:
Abstract T-cell acute lymphoblastic leukemia (T-ALL) is a malignancy of immature T cell progenitors in which we described activating mutations of Notch1 to occur in over 50% of cases. As well, others have identified loss-of-function mutations in Sel10/Fbw7 to occur in 8–16% of cases, which also enhance Notch signaling. Notably, inhibition of Notch signaling in these cells induces growth arrest and in some cases apoptosis as well. Subsequent studies have characterized c-myc as a critical downstream target of Notch signaling in this context. More recently, mutations in PTEN (occurring in 17% of cases) were shown to potentiate PI3K/Akt signaling and proposed to confer resistance to Notch signaling inhibition, but then impose “addiction” to PI3K/Akt. Most leukemias likely derive cooperative growth/survival signals from Notch and PI3K/Akt pathways, as evidenced by synergistic effects of gamma-secretase inhibitors (GSI) which block Notch signaling and rapamycin which blocks mTOR downstream of PI3K/Akt. In mouse models, combined activation of c-myc and b-catenin with inactivation of PTEN elicited T-ALL which was devoid of Notch mutations, suggesting Notch signaling coordinately activates c-myc, Wnt, and PI3K/Akt signaling pathways. In studying the mechanism for PI3K/Akt activation in T-ALL with activated Notch signaling, we examined insulin-like growth factor receptor-1 (IGF1R) as a candidate upstream initiator of PI3K/Akt activation. We observed IGF1R expression consistently in T-ALL cells from primary human leukemias and cell lines, as well as in primary mouse leukemias derived experimentally by retroviral transduction of marrow with activated forms of Notch1. In all cases, inhibition of IGF1R signaling either with blocking antibody or small molecule kinase inhibitors resulted in growth suppression and apoptosis of leukemia cells. We further observed that inhibition of Notch signaling either by small molecule GSI or transduction with a dominant negative coactivator, Mastermind, resulted in a 2–3 fold decrease in IGF1R expression. Given that the PI3K/Akt/mTOR pathway is known to be important for growth/survival of T-ALL leukemia cells, we hypothesized that Notch might be potentiating activation of this pathway by upregulating IGF1R expression. In fact, we found leukemia cells with active Notch and higher IGF1R levels showed 20-fold greater sensitivity to IGF-1 ligand induced Akt activation as compared to leukemia cells with inactive Notch and lower IGF1R levels. This enhanced signaling output cannot be explained by Notch suppression of PTEN as this effect was noted in both PTEN wild-type and PTEN null leukemia cells. Additionally, cells with wild type PTEN demonstrated only minimal if any changes in PTEN protein levels after Notch inhibition as measured by a highly quantitative flow cytometry assay. In sum, we have identified IGF-1 signaling as being critical to growth and survival of T-ALL leukemia cells, and provide evidence that Notch may potentiate PI3K/Akt signaling by upregulating expression of IGF1R. These data are of immediate clinical relevance as several IGF1R inhibitors are currently in Phase 3 clinical trial and hopefully will provide additional therapeutic options to refractory/relapsed patients and/or in combination with front-line therapy in newly diagnosed patients.
13
Gounari, Fotini, and Marei Dose. "Lef-1: NOTCHed up in T-cell lymphomas." Blood 110, no. 7 (October 1, 2007): 2227. http://dx.doi.org/10.1182/blood-2007-07-100156.
Повний текст джерелаАнотація:
In this issue of Blood, Spaulding and colleagues show that Lef-1, one of the transcription factors mediating Wnt signaling, is a transcriptional target of Notch in T-cell lymphomas. Notch-activating mutations are commonly found in human T-lineage acute lymphoblastic leukemia (T-ALL) cases, while activation of Wnt/β-catenin signaling has recently been shown to induce T-cell leukemia in mice. The proposed regulation of Lef-1 transcription by Notch suggests the intriguing possibility that the Notch and Wnt pathways are closely intertwined in the etiology of T-cell leukemia.
14
Weng, Andrew P., and Arthur Lau. "Notch signaling in T-cell acute lymphoblastic leukemia." Future Oncology 1, no. 4 (August 2005): 511–19. http://dx.doi.org/10.2217/14796694.1.4.511.
Повний текст джерела
15
Alshaer, Walhan, Dana A. Alqudah, Suha Wehaibi, Duaa Abuarqoub, Malek Zihlif, Ma’mon M. Hatmal та Abdalla Awidi. "Downregulation of STAT3, β-Catenin, and Notch-1 by Single and Combinations of siRNA Treatment Enhance Chemosensitivity of Wild Type and Doxorubicin Resistant MCF7 Breast Cancer Cells to Doxorubicin". International Journal of Molecular Sciences 20, № 15 (28 липня 2019): 3696. http://dx.doi.org/10.3390/ijms20153696.
Повний текст джерелаАнотація:
Combinatorial therapeutic strategies using siRNA and small molecules to eradicate tumors are emerging. Targeting multiple signaling pathways decreases the chances of cancer cells switching and adapting new signaling processes that may occur when using a single therapeutic modality. Aberrant functioning of Notch-1, Wnt/β-catenin, and STAT3 proteins and their crosstalk signaling pathways have been found to be involved in tumor survival, drug resistance, and relapse. In the current study, we describe a therapeutic potential of single and combinations of siRNA designed for silencing Notch-1, Wnt/β-catenin, and STAT3 in MCF7_DoxS (wild type) and MCF7_DoxR (doxorubicin resistant) breast cancer cells. The MCF7_DoxR cells were developed through treatment with a gradual increase in doxorubicin concentration, the expression of targeted genes was investigated, and the expression profiling of CD44/CD24 of the MCF7_DoxS and MCF7_DoxR cells were detected by flow cytometry. Both MCF7_DoxS and MCF7_DoxR breast cancer cells were treated with single and combinations of siRNA to investigate synergism and were analyzed for their effect on cell proliferation with and without doxorubicin treatment. The finding of this study showed the overexpression of targeted genes and the enrichment of the CD44−/CD24+ phenotype in MCF7_DoxR cells when compared to MCF7_DoxS cells. In both cell lines, the gene silencing efficacy showed a synergistic effect when combining STAT3/Notch-1 and STAT3/Notch-1/β-catenin siRNA. Interestingly, the chemosensitivity of MCF7_DoxS and MCF7_DoxR cells to doxorubicin was increased when combined with siRNA treatment. Our study shows the possibility of using single and combinations of siRNA to enhance the chemosensitivity of cancer cells to conventional antitumor chemotherapy.
16
Lehal, Rajwinder, Jelena Zaric, Michele Vigolo, Charlotte Urech, Viktoras Frismantas, Nadine Zangger, Linlin Cao, et al. "Pharmacological disruption of the Notch transcription factor complex." Proceedings of the National Academy of Sciences 117, no. 28 (June 29, 2020): 16292–301. http://dx.doi.org/10.1073/pnas.1922606117.
Повний текст джерелаАнотація:
Notch pathway signaling is implicated in several human cancers. Aberrant activation and mutations of Notch signaling components are linked to tumor initiation, maintenance, and resistance to cancer therapy. Several strategies, such as monoclonal antibodies against Notch ligands and receptors, as well as small-molecule γ-secretase inhibitors (GSIs), have been developed to interfere with Notch receptor activation at proximal points in the pathway. However, the use of drug-like small molecules to target the downstream mediators of Notch signaling, the Notch transcription activation complex, remains largely unexplored. Here, we report the discovery of an orally active small-molecule inhibitor (termed CB-103) of the Notch transcription activation complex. We show that CB-103 inhibits Notch signaling in primary human T cell acute lymphoblastic leukemia and other Notch-dependent human tumor cell lines, and concomitantly induces cell cycle arrest and apoptosis, thereby impairing proliferation, including in GSI-resistant human tumor cell lines with chromosomal translocations and rearrangements in Notch genes. CB-103 produces Notch loss-of-function phenotypes in flies and mice and inhibits the growth of human breast cancer and leukemia xenografts, notably without causing the dose-limiting intestinal toxicity associated with other Notch inhibitors. Thus, we describe a pharmacological strategy that interferes with Notch signaling by disrupting the Notch transcription complex and shows therapeutic potential for treating Notch-driven cancers.
17
Weng, Andrew P., Yunsun Nam, Michael S. Wolfe, Warren S. Pear, James D. Griffin, Stephen C. Blacklow, and Jon C. Aster. "Growth Suppression of Pre-T Acute Lymphoblastic Leukemia Cells by Inhibition of Notch Signaling." Molecular and Cellular Biology 23, no. 2 (January 15, 2003): 655–64. http://dx.doi.org/10.1128/mcb.23.2.655-664.2003.
Повний текст джерелаАнотація:
ABSTRACT Constitutive NOTCH signaling in lymphoid progenitors promotes the development of immature T-cell lymphoblastic neoplasms (T-ALLs). Although it is clear that Notch signaling can initiate leukemogenesis, it has not previously been established whether continued NOTCH signaling is required to maintain T-ALL growth. We demonstrate here that the blockade of Notch signaling at two independent steps suppresses the growth and survival of NOTCH1-transformed T-ALL cells. First, inhibitors of presenilin specifically induce growth suppression and apoptosis of a murine T-ALL cell line that requires presenilin-dependent proteolysis of the Notch receptor in order for its intracellular domain to translocate to the nucleus. Second, a 62-amino-acid peptide derived from a NOTCH coactivator, Mastermind-like-1 (MAML1), forms a transcriptionally inert nuclear complex with NOTCH1 and CSL and specifically inhibits the growth of both murine and human NOTCH1-transformed T-ALLs. These studies show that continued growth and survival of NOTCH1-transformed lymphoid cell lines require nuclear access and transcriptional coactivator recruitment by NOTCH1 and identify at least two steps in the Notch signaling pathway as potential targets for chemotherapeutic intervention.
18
Bassi, Giulio, Paul Takam Kamga, Armel Nwabo Kamdje, Roberta Stradoni, Giorgio Malpeli, Eliana Amati, Ilaria Nichele, et al. "Role Of Stromal Cell-Mediated Notch Signaling In Hematological Malignancies." Blood 122, no. 21 (November 15, 2013): 4939. http://dx.doi.org/10.1182/blood.v122.21.4939.4939.
Повний текст джерелаАнотація:
Abstract Stromal cells are essential components of the bone marrow (BM) microenvironment regulating and supporting the survival of different tumors, including B-cell acute and chronic lymphocytic leukemia (B-ALL and CLL), and acute myeloid leukemia (AML). In this study, we investigated the role of Notch signalling in human BM-mesenchymal stromal cell (hBM-MSC)-promoted ALL, CLL and AML survival and chemoresistance. The block of Notch signalling through γ-secretase inhibitor (GSI) XII reverted the protective effect mediated by co-culture with BM-MSC. The treatment with combinations of anti-Notch neutralizing Abs resulted in the decrease of B-ALL cell survival, either cultured alone or cocultured in presence of BM-MSC from normal donors and B-ALL patients. The inhibition of Notch-3 and -4 or Jagged-1/-2 and DLL-1 resulted in a dramatic increase of apoptotic B-ALL cells by 3 days, similar to what is obtained by blocking all Notch signaling with the GSI XII. The same Notch receptors are involved in CLL survival except for Notch-1 that, in CLL, mediates a synergistic effect with other Notch receptors in inducing the anti-apoptotic phenotype. Some preliminary data showed that Notch system is involved in survival and chemoresistance of acute myeloid leukemia blasts. Overall, our findings show that stromal cell-mediated Notch signaling has a role in promoting ALL, CLL and AML survival and resistance to chemotherapy. Therefore, the target of Notch pathway activation may represent a useful strategy to overcome drug resistance and improve the efficacy of conventional treatments. Disclosures: No relevant conflicts of interest to declare.
19
Lobry, Camille, Philmo Oh, Marc R. Mansour, A. Thomas Look, and Iannis Aifantis. "Notch signaling: switching an oncogene to a tumor suppressor." Blood 123, no. 16 (April 17, 2014): 2451–59. http://dx.doi.org/10.1182/blood-2013-08-355818.
Повний текст джерелаАнотація:
Abstract The Notch signaling pathway is a regulator of self-renewal and differentiation in several tissues and cell types. Notch is a binary cell-fate determinant, and its hyperactivation has been implicated as oncogenic in several cancers including breast cancer and T-cell acute lymphoblastic leukemia (T-ALL). Recently, several studies also unraveled tumor-suppressor roles for Notch signaling in different tissues, including tissues where it was before recognized as an oncogene in specific lineages. Whereas involvement of Notch as an oncogene in several lymphoid malignancies (T-ALL, B-chronic lymphocytic leukemia, splenic marginal zone lymphoma) is well characterized, there is growing evidence involving Notch signaling as a tumor suppressor in myeloid malignancies. It therefore appears that Notch signaling pathway’s oncogenic or tumor-suppressor abilities are highly context dependent. In this review, we summarize and discuss latest advances in the understanding of this dual role in hematopoiesis and the possible consequences for the treatment of hematologic malignancies.
20
Wang, Weiwei, Tetsuya Okajima, and Hideyuki Takeuchi. "Significant Roles of Notch O-Glycosylation in Cancer." Molecules 27, no. 6 (March 9, 2022): 1783. http://dx.doi.org/10.3390/molecules27061783.
Повний текст джерелаАнотація:
Notch signaling, which was initially identified in Drosophila wing morphogenesis, plays pivotal roles in cell development and differentiation. Optimal Notch pathway activity is essential for normal development and dysregulation of Notch signaling leads to various human diseases, including many types of cancers. In hematopoietic cancers, such as T-cell acute lymphoblastic leukemia, Notch plays an oncogenic role, while in acute myeloid leukemia, it has a tumor-suppressive role. In solid tumors, such as hepatocellular carcinoma and medulloblastoma, Notch may have either an oncogenic or tumor-suppressive role, depending on the context. Aberrant expression of Notch receptors or ligands can alter the ligand-dependent Notch signaling and changes in trafficking can lead to ligand-independent signaling. Defects in any of the two signaling pathways can lead to tumorigenesis and tumor progression. Strikingly, O-glycosylation is one such process that modulates ligand–receptor binding and trafficking. Three types of O-linked modifications on the extracellular epidermal growth factor-like (EGF) repeats of Notch receptors are observed, namely O-glucosylation, O-fucosylation, and O-N-acetylglucosamine (GlcNAc) modifications. In addition, O-GalNAc mucin-type O-glycosylation outside the EGF repeats also appears to occur in Notch receptors. In this review, we first briefly summarize the basics of Notch signaling, describe the latest information on O-glycosylation of Notch receptors classified on a structural basis, and finally describe the regulation of Notch signaling by O-glycosylation in cancer.
21
Gusscott, Samuel D., Florian Kuchenbauer, and Andrew P. Weng. "Notch Signaling Represses Mir-223 in T-Cell Acute Lymphoblastic Leukemia." Blood 118, no. 21 (November 18, 2011): 4630. http://dx.doi.org/10.1182/blood.v118.21.4630.4630.
Повний текст джерелаАнотація:
Abstract Abstract 4630 T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer of immature T cells that often shows aberrant activation of the Notch1 signaling pathway. Several studies have utilized mRNA expression profiling to identify downstream mediators of oncogenic Notch signaling in this context. Since microRNAs (miRNAs) have in recent years been shown to play important roles in hematological maliganancy, we performed a microarray-based screen for Notch-dependent miRNA expression in T-ALL. Jurkat and P12-Ichikawa cell lines were treated with gamma-secretase inhibitor to block Notch signaling vs. DMSO control for 4 days and profiled using Exigon miRCURY LNA miRNA microarrays. Surprisingly few miRNAs were found to be regulated by this approach; however, one of the hits, miR-223, showed consistent upregulation after gamma-secretase treatment in Jurkat cells and 5 additional human T-ALL cell lines assessed by miRNA qPCR. This observation was unique to human T-ALL as murine models of T-ALL showed no evidence for Notch-dependent miR-223 expression. Given that canonical Notch signaling results in transcriptional activation, our observation that Notch signaling is associated with reduced miR-223 expression suggests an intermediary repressor may be involved. miR-223 has been reported to play an important role in normal granulopoiesis, to be expressed relatively highly in T-ALL with myeloid-like gene features, and most recently to accelerate Notch-mediated T-cell leukemogenesis. To explore potential functional consequences for Notch-dependent miR-223 repression in T-ALL, candidate miR-223 targets identified by TargetScan software were analyzed with Ingenuity Pathway Analysis software, which indicated IGF-1, insulin receptor, PTEN, and ERK5 signaling pathways as the top hits. We recently reported IGF1R signaling to be important for growth and viability of bulk T-ALL cells as well as for leukemia-initiating cell activity. Additionally, we reported that Notch signaling directly upregulates IGF1R transcription by binding to an intronic enhancer which is present between exons 21/22 in the human, but not mouse IGF1R locus. As miR-223 has previously been reported to target IGF1R mRNA and reduce its translation, we hypothesized that Notch signaling may also upregulate net IGF1R protein expression by repressing miR-223. To test this hypothesis, we transduced several human T-ALL cell lines with miR-223 retrovirus and observed a modest decrease in total IGF1R protein levels by western blot; however, no significant change was observed in surface IGF1R levels as assessed by flow cytometry. Addtionally, knockdown of miR-223 by lentiviral expression miR-223 target sequences (miR-223 “sponge”) resulted in modestly increased total IGF1R protein levels, but again showed no demonstrable effect on surface IGF1R levels. Of note, we also observed no apparent effect of either overexpression or knockdown of miR-223 on bulk cell growth or viability. We interpret these findings to suggest that Notch signaling does not have major effects on the miR transcriptome, and that up- or down-modulation of miR-223 in established T-ALL cells does not have significant effects on overall cell growth/viability. Further studies will be required to determine if miR-223 may act in concert with other Notch target genes to modulate cell physiology. Disclosures: No relevant conflicts of interest to declare.
22
Pinto, Inês, Mafalda Duque, Joana Gonçalves, Padma Akkapeddi, Mariana L. Oliveira, Rita Cabrita, J. Andrés Yunes, Scott K. Durum, João T. Barata, and Rita Fragoso. "NRARP displays either pro- or anti-tumoral roles in T-cell acute lymphoblastic leukemia depending on Notch and Wnt signaling." Oncogene 39, no. 5 (October 4, 2019): 975–86. http://dx.doi.org/10.1038/s41388-019-1042-9.
Повний текст джерелаАнотація:
Abstract T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with a dismal prognosis in patients with resistant or relapsed disease. Although NOTCH is a known driver in T-ALL, its clinical inhibition has significant limitations. Our previous studies suggested that NRARP, a negative regulator of Notch signaling, could have a suppressive role in T-ALL. Here, we report that NRARP levels are significantly increased in primary T-ALL cells suggesting that NRARP is not sufficient to block NOTCH oncogenic signals. Interestingly, although NRARP overexpression blocks NOTCH1 signaling and delays the proliferation of T-ALL cells that display high levels of Notch1 signaling, it promotes the expansion of T-ALL cells with lower levels of Notch1 activity. We found that NRARP interacts with lymphoid enhancer-binding factor 1 (LEF1) and potentiates Wnt signaling in T-ALL cells with low levels of Notch. Together these results indicate that NRARP plays a dual role in T-ALL pathogenesis, regulating both Notch and Wnt pathways, with opposite functional effects depending on Notch activity. Consistent with this hypothesis, mice transplanted with T-cells co-expressing NOTCH1 and NRARP develop leukemia later than mice transplanted with T-NOTCH1 cells. Importantly, mice transplanted with T-cells overexpressing NRARP alone developed leukemia with similar kinetics to those transplanted with T-NOTCH1 cells. Our findings uncover a role for NRARP in T-ALL pathogenesis and indicate that Notch inhibition may be detrimental for patients with low levels of Notch signaling, which would likely benefit from the use of Wnt signaling inhibitors. Importantly, our findings may extend to other cancers where Notch and Wnt play a role.
23
Lee, Keunwook, Ki Taek Nam, Sung Hoon Cho, Prathyusha Gudapati, Yoonha Hwang, Do-Sim Park, Ross Potter, Jin Chen, Emmanuel Volanakis, and Mark Boothby. "Vital roles of mTOR complex 2 in Notch-driven thymocyte differentiation and leukemia." Journal of Experimental Medicine 209, no. 4 (April 2, 2012): 713–28. http://dx.doi.org/10.1084/jem.20111470.
Повний текст джерелаАнотація:
Notch plays critical roles in both cell fate decisions and tumorigenesis. Notch receptor engagement initiates signaling cascades that include a phosphatidylinositol 3-kinase/target of rapamycin (TOR) pathway. Mammalian TOR (mTOR) participates in two distinct biochemical complexes, mTORC1 and mTORC2, and the relationship between mTORC2 and physiological outcomes dependent on Notch signaling is unknown. In this study, we report contributions of mTORC2 to thymic T-cell acute lymphoblastic leukemia (T-ALL) driven by Notch. Conditional deletion of Rictor, an essential component of mTORC2, impaired Notch-driven proliferation and differentiation of pre-T cells. Furthermore, NF-κB activity depended on the integrity of mTORC2 in thymocytes. Active Akt restored NF-κB activation, a normal rate of proliferation, and differentiation of Rictor-deficient pre-T cells. Strikingly, mTORC2 depletion lowered CCR7 expression in thymocytes and leukemic cells, accompanied by decreased tissue invasion and delayed mortality in T-ALL driven by Notch. Collectively, these findings reveal roles for mTORC2 in promoting thymic T cell development and T-ALL and indicate that mTORC2 is crucial for Notch signaling to regulate Akt and NF-κB.
24
Takam Kamga, Paul, Giada Dal Collo, Federica Resci, Riccardo Bazzoni, Angela Mercuri, Francesca Maria Quaglia, Ilaria Tanasi, et al. "Notch Signaling Molecules as Prognostic Biomarkers for Acute Myeloid Leukemia." Cancers 11, no. 12 (December 6, 2019): 1958. http://dx.doi.org/10.3390/cancers11121958.
Повний текст джерелаАнотація:
The role of Notch signaling in acute myeloid leukemia (AML) is still under investigation. We have previously shown that high levels of Notch receptors and ligands could interfere with drug response. In this study, the protein expression of 79 AML blast samples collected from newly diagnosed patients was examined through flow cytometry. Gamma-secretase inhibitors were used in AML mouse xenograft models to evaluate the contribution of Notch pharmacological inhibition to mouse survival. We used univariate analysis for testing the correlation and/or association between protein expression and well-known prognostics markers. All the four receptors (Notch1–4) and some ligands (Jagged2, DLL-3) were highly expressed in less mature subtypes (M0–M1). Notch3, Notch4, and Jagged2 were overexpressed in an adverse cytogenetic risk group compared to good cytogenetic risk patients. Chi-square analysis revealed a positive association between the complete remission rate after induction therapy and weak expression of Notch2 and Notch3. We also found an association between low levels of Notch4 and Jagged2 and three-year remission following allogeneic stem cell transplantation (HSCT). Accordingly, Kaplan–Meier analysis showed improved OS for patients lacking significant expression of Notch4, Jagged2, and DLL3. In vivo experiments in an AML mouse model highlighted both improved survival and a significant reduction of leukemia cell burden in the bone marrow of mice treated with the combination of Notch pan-inhibitors (GSIs) plus chemotherapy (Ara-C). Our results suggest that Notch can be useful as a prognostic marker and therapeutic target in AML.
25
Aifantis, Iannis. "The Notch Signaling Pathway as a Suppressor of Myeloid Transformation." Blood 118, no. 21 (November 18, 2011): SCI—13—SCI—13. http://dx.doi.org/10.1182/blood.v118.21.sci-13.sci-13.
Повний текст джерелаАнотація:
Abstract Abstract SCI-13 Notch signaling is a central regulator of differentiation in a variety of organisms and tissue types. Its activity is controlled by the multi-subunit γ-secretase complex (γSE) complex. Although Notch signaling can play both oncogenic and tumor suppressor roles in solid tumors, in the hematopoietic system, it is exclusively oncogenic, notably in T cell acute lymphoblastic leukemia (T-ALL), a disease characterized by Notch1 activating mutations. We identified somatic inactivating Notch pathway mutations in a fraction of chronic myelomonocytic leukemia (CMML) patients. Inactivation of Notch signaling in mouse hematopoietic stem cells (HSC) results in an aberrant accumulation of granulocyte/monocyte progenitors (GMP), extramedullary hematopoieisis and the induction of CMML-like disease. Transcriptome analysis reveals that Notch signaling regulates an extensive myelomonocytic-specific gene signature, through the direct suppression of gene transcription by the Notch target Hes1. These studies identify a novel role for Notch signaling during early hematopoietic stem cell differentiation and suggest that the Notch pathway can play both tumor-promoting and suppressive roles within the same tissue. These observations also suggest that Notch activity is not simply a promoter of the T cell lineage in the thymus but that Notch signaling thresholds could regulate commitment and/or survival of distinct hematopoietic lineages in the bone marrow. To address these issues in vivo, we have generated Notch receptor lineage tracing and activity reporter genetic tools. Analysis of these animal models identified unique novel functions for the Notch pathway during early bone marrow hematopoiesis. Disclosures: No relevant conflicts of interest to declare.
26
Li, Xiaoyu, and Harald von Boehmer. "Notch Signaling in T-Cell Development and T-ALL." ISRN Hematology 2011 (January 23, 2011): 1–9. http://dx.doi.org/10.5402/2011/921706.
Повний текст джерелаАнотація:
The Notch signaling pathway is an evolutionarily conserved cell signaling system present in most multicellular organisms, as it controls cell fate specification by regulating cell proliferation, differentiation, apoptosis, and survival. Regulation of the Notch signaling pathway can be achieved at multiple levels. Notch proteins are involved in lineage fate decisions in a variety of tissues in various species. Notch is essential for T lineage cell differentiation including T versus B and αβ versus γδ lineage specification. In this paper, we discuss Notch signaling in normal T-cell maturation and differentiation as well as in T-cell acute lymphoblastic lymphoma/leukemia.
27
Takam Kamga, Paul, Federica Resci, Giada Dal Collo, Annalisa Adamo, Riccardo Bazzoni, Angela Mercuri, Massimiliano Bonifacio, and Mauro Krampera. "Prognostic Impact of Notch Signaling in Acute Myeloid Leukemia (AML)." Blood 132, Supplement 1 (November 29, 2018): 5242. http://dx.doi.org/10.1182/blood-2018-99-118701.
Повний текст джерелаАнотація:
Abstract Background: Notch signaling is a developmental pathway involved in normal and malignant hematopoiesis. Mutations in Notch genes lead to T-ALL and are associated with poor prognosis in B-CLL. However its role in AML is still under investigation, with controversial results. In addition, although the pathway consists of 4 receptors and 5 ligands, many studies are mostly based on single receptor or ligand. Aims: This study was conducted to determine if the expression level of each Notch receptor and ligand are associated with known prognostic factors and patient's survival. Methods: AML primary cells were collected from 79 AML patients after informed consent. The follow-up was for 36 months. Flow cytometry analysis was used to study the expression of each Notch receptor and ligand. Prognostics or risk factors considered were sex, white blood counts, FAB and cytogenetics. The Mann-Whitney test was used for analyzing differences in expression levels between two groups. Spearman test was used for correlation between Notch expression levels and prognostics factors. Differences in overall (OS) and progression free (PFS) survival were established through Gehan-Breslow-Wilcoxon test. Results: Consistently with previous findings, we found expression of Notch1, Notch2, Notch3, Notch4, Jagged1, Jagged2 and DLL3 in AML samples. There were no differences in expression levels between male and female. For each receptor or ligand, higher expression levels were found in more immature samples (M0, M1, and M2). Notch3, Notch4 and Jagged2 were enriched in adverse cytogenenetics risk groups compared to favorable cytogenetics risk patients. Then, for each receptor or ligand, patients were divided into two groups; patients with higher expression levels and patients with lower expression levels. Analyzing OS and PFS, we found that patients with lower expression levels of Notch4, Jagged2 and DLL3 displayed a longer survival compared to patients with higher expression levels. Conclusion: Given its oncogenic role in T-ALL and other malignancies Notch1 has been the more studied receptors in hematological malignancies. However, we have previously demonstrated that Notch4, DLL3 and Jagged2 are all involved in survival of AML and B-ALL cells. Studying the prognostic value of all Notch receptors and ligands, the current research clearly shows that higher levels of Notch4 and Jagged2 are found in poor cytogenetics risk groups and are associated with a shorter patient's survival. These demonstrations suggest that expression levels of Notch receptors and ligands in AML patient's samples at diagnostic could stand as prognostic marker for clinical care. Disclosures No relevant conflicts of interest to declare.
28
Zweidler-McKay, Patrick A., Yiping He, Lanwei Xu, Carlos G. Rodriguez, Fredrick G. Karnell, Andrea C. Carpenter, Jon C. Aster, David Allman, and Warren S. Pear. "Notch signaling is a potent inducer of growth arrest and apoptosis in a wide range of B-cell malignancies." Blood 106, no. 12 (December 1, 2005): 3898–906. http://dx.doi.org/10.1182/blood-2005-01-0355.
Повний текст джерелаАнотація:
Although Notch receptor expression on malignant B cells is widespread, the effect of Notch signaling in these cells is poorly understood. To investigate Notch signaling in B-cell malignancy, we assayed the effect of Notch activation in multiple murine and human B-cell tumors, representing both immature and mature subtypes. Expression of constitutively active, truncated forms of the 4 mammalian Notch receptors (ICN1-4) inhibited growth and induced apoptosis in both murine and human B-cell lines but not T-cell lines. Similar results were obtained in human precursor B-cell acute lymphoblastic leukemia lines when Notch activation was achieved by coculture with fibroblasts expressing the Notch ligands Jagged1 or Jagged2. All 4 truncated Notch receptors, as well as the Jagged ligands, induced Hes1 transcription. Retroviral expression of Hairy/Enhancer of Split-1 (Hes1) recapitulated the Notch effects, suggesting that Hes1 is an important mediator of Notch-induced growth arrest and apoptosis in B cells. Among the B-cell malignancies that were susceptible to Notch-mediated growth inhibition/apoptosis were mature B-cell and therapy-resistant B-cell malignancies, including Hodgkin, myeloma, and mixed-lineage leukemia (MLL)–translocated cell lines. These results suggest that therapies capable of activating Notch/Hes1 signaling may have therapeutic potential in a wide range of human B-cell malignancies.
29
Lake, Robert J., Mark K. Haynes, Kostiantyn Dreval, Rabeya Bilkis, Larry A. Sklar, and Hua-Ying Fan. "A Novel Flow Cytometric Assay to Identify Inhibitors of RBPJ-DNA Interactions." SLAS DISCOVERY: Advancing the Science of Drug Discovery 25, no. 8 (June 22, 2020): 895–905. http://dx.doi.org/10.1177/2472555220932552.
Повний текст джерелаАнотація:
Notch signaling is often involved in cancer cell initiation and proliferation. Aberrant Notch activation underlies more than 50% of T-cell acute lymphoblastic leukemia (T-ALL); accordingly, chemicals disrupting Notch signaling are of potential to treat Notch-dependent cancer. Here, we developed a flow cytometry-based high-throughput assay to identify compounds that disrupt the interactions of DNA and RBPJ, the major downstream effector of Notch signaling. From 1492 compounds, we identified 18 compounds that disrupt RBPJ-DNA interactions in a dose-dependent manner. Cell-based assays further revealed that auranofin downregulates Notch-dependent transcription and decreases RBPJ–chromatin interactions in cells. Most strikingly, T-ALL cells that depend on Notch signaling for proliferation are more sensitive to auranofin treatment, supporting the notion that auranofin downregulates Notch signaling by disrupting RBPJ-DNA interaction. These results validate the feasibility of our assay scheme to screen for additional Notch inhibitors and provide a rationale to further test the use of auranofin in treating Notch-dependent cancer.
30
Chiang, Mark Y., Olga Shestova, M. Eden Childs, Candice Romany, Jon Aster, and Warren S. Pear. "Divergent Effects of Notch Signaling On Leukemia Stem Cells and Hematopoietic Stem Cells." Blood 114, no. 22 (November 20, 2009): 395. http://dx.doi.org/10.1182/blood.v114.22.395.395.
Повний текст джерелаАнотація:
Abstract Abstract 395 The Leukemia Stem Cell (LSC) hypothesis proposes that a subset of the cells in the bulk tumor cell population is responsible for leukemia maintenance and propagation. We tested the LSC hypothesis in murine T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) induced by retroviruses expressing strong gain-of-function Notch1 alleles. This model is relevant to human disease, as Notch1 is activated in ∼70% of human T-ALLs. By transferring sorted leukemia cells to syngeneic secondary recipients at limiting dilution, we found that LSC activity was enriched in the CD8+CD4-HSAhi (Immature Single Positive or “ISP”) T-cell subset. The LSC frequency was ∼1 in 1000 cells, two orders of magnitude higher than in the CD8+CD4+ (Double positive or “DP”) T-cell subset. We found similar results in a KrasG12D-driven T-ALL mouse model where activating Notch mutations occur spontaneously in ∼80% cases. Surprisingly, we were unable to isolate Notch-activated hematopoietic stem and progenitor cells (HSPCs) to test for LSC activity. Upon further analysis, we observed that activation of Notch in HSPCs caused loss of stem cell quiescence and progressive, complete loss of long-term hematopoietic stem cells (LT-HSCs) over several weeks. Notch signals had no significant effects on stem cell homing, apoptosis, or senescence. Similar results were obtained in both noncompetitive and competitive secondary transplants as well as in a mouse model in which Notch activation is conditionally induced in HSCs by Cre recombinase. We conclude that while Notch signaling promotes LSC activity, it extinguishes HSCs. These results provide a rationale for therapeutic targeting of the ISP-like T-cell subset in Notch-activated T-ALL while underscoring the potential difficulty of manipulating Notch signaling to expand normal, long-term stem cell populations for clinical applications. Disclosures: No relevant conflicts of interest to declare.
31
Lee, Keunwook, Prathyusha Gudapati, Emmanuel Volanakis, Sunghoon Cho, and Mark Boothby. "mTOR complex 2 mediates Notch signaling in thymocyte and T-cell leukemia development (64.8)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 64.8. http://dx.doi.org/10.4049/jimmunol.186.supp.64.8.
Повний текст джерелаАнотація:
Abstract Mammalian target of rapamycin (mTOR) is an important component of the PI3-kinase (PI3K) pathway that regulates cell growth and proliferation. PI3K signaling cascades can be initiated by activation of Notch, a critical regulator for T lineage commitment and leukemia development. Here we show that mTOR complex 2 (mTORC2) is functionally vital as a downstream target of Notch in thymocytes and T-cell acute lymphoblastic leukemia (T-ALL). Conditional deletion of rictor, an essential component of mTORC2, results in impaired proliferation and differentiation of pre-T cells driven by Notch ligation. Moreover, mTORC2 is a primary kinase for Akt S473 and enhances Akt activity in thymocytes. Furthermore, mTORC2 regulates NF-κB activity, such that constitutively active Akt can restore nuclear NF-κB levels in the rictor-depleted pre-T cells, as well as normalizing Notch-initiated proliferation and differentiation. Strikingly, interruption of mTORC2 significantly delays T-ALL induced by Notch1 activating mutation and suppresses infiltration of leukemic cells into the non-lymphoid organs. Our study provides evidence of a key role of mTORC2 in relaying Notch signaling in thymocyte development, and reveals that mTORC2 promotes Notch-driven leukemia progression.
32
Grieselhuber, Nicole R., Jeffery M. Klco, Angela M. Verdoni, and Timothy J. Ley. "Activation of Notch Signaling Is An Early Event in the Development of PML-Rara-Induced Acute Promyelocytic Leukemia (APL)." Blood 118, no. 21 (November 18, 2011): 2468. http://dx.doi.org/10.1182/blood.v118.21.2468.2468.
Повний текст джерелаАнотація:
Abstract Abstract 2468 Acute promyelocytic leukemia (APL, FAB M3) is characterized by the presence of the t(15;17) translocation, resulting in production of the oncogenic transcription factor PML-RARA. We previously reported a gene expression signature of 1121 annotated genes that distinguish APL from the other FAB subtypes and normal promyelocytes (Payton et al, JCI 2009). Within this signature, we identified the Notch ligand JAG1 as being overexpressed in APL samples compared to both other AML subtypes (APL/AML=4.2, FDR<0.5%) and normal promyelocytes (APL/pros=5.66, FDR<0.5%). We then measured JAG1 expression in mouse and cellular models of APL. High levels of JAG1 mRNA and protein were found in both zinc treated PR9 cells (which contain a zinc inducible PML-RARA cassette), and in NB4 cells, a human APL cell line. APL cells derived from the mCG-PML-RARA knockin mouse overexpressed Jag1 mRNA compared to wildtype promyelocytes (APL/pros=10.4, p<0.01). Additionally, Jag1 protein was readily detected in up to 90% of murine APL cells by flow cytometry. Collectively, these results indicate that JAG1 overexpression is a common event in both human and murine APL pathogenesis. Hypothesizing that JAG1 overexpression could lead to Notch signaling in APL cells, we measured Notch signaling in human and murine APL cells. The Notch receptors Notch-1 and Notch-2, the components of the gamma secretase complex, and the transcriptional coactivators of Notch are highly expressed in nearly all human APL samples, suggesting that APL cells are capable of Notch signaling. Using bioinformatic approaches, we found that three previously defined activated Notch signatures were significantly enriched in APL cells (FDR=0.00) and also in PR9 and NB4 cells. Protein levels of cleaved Notch-1 increased in induced PR9 cells with the same kinetics as JAG1 protein, peaking at 16 hours post-induction. In addition, flow cytometry demonstrated the presence of cleaved Notch protein in PR9 and NB4 cells, and both primary and immortalized murine APL samples. To define the consequences of inhibiting Notch signaling in APL cells, we cultured primary murine APL cells in the presence of gamma secretase inhibitors; colony formation in 6/9 tumors was significantly inhibited (p<0.05). Growth of primary murine marrow and spleen cells was unaffected under identical culture conditions. Finally, we investigated the role of Notch signaling in APL pathogenesis in young mCG-PR mice prior to the development of leukemia. Marrow derived progenitors from PML-RARA mice replate serially in methylcellulose cultures, in contrast to wildtype marrow cells, which do not replate. In contrast to primary tumor cells, which were variably dependent on Notch signaling, preleukemic cells were uniformly dependent on Notch signaling for replating activity. In the presence of gamma secretase inhibitors, the replating phenotype is significantly decreased (p<0.01). In contrast, colony formation by wildtype cells is unaffected by inhibition of Notch signaling. Similarly, when Notch signaling in primary marrow cells was genetically inhibited by retroviral transduction of a dominant negative mastermind construct (DNMAML), colony formation by PML-RARA cells was significantly decreased at the first, second and third replatings compared to GFP control cells (p<0.01). Again, wildtype marrow colony formation was unaffected by DNMAML transduction. Importantly, wild type marrow cells transduced with a JAG1 expressing retrovirus did not acquire a replating phenotype, nor did animals transplanted with JAG1 expressing marrow develop leukemia. In conclusion, we have demonstrated overexpression of JAG1 and activation of Notch signaling in human and murine APL cells, and have shown that Notch signaling may play a role in the early pathogenesis of APL. Collectively, these results support a model in which PML-RARA induces the self-renewal of hematopoietic progenitors via a Notch signaling pathway, which may be a critical early step in APL pathogenesis. Disclosures: No relevant conflicts of interest to declare.
33
Pear, Warren S. "Notch and Leukemia: Lessons from Mouse Models." Blood 112, no. 11 (November 16, 2008): sci—31—sci—31. http://dx.doi.org/10.1182/blood.v112.11.sci-31.sci-31.
Повний текст джерелаАнотація:
Mammalian Notch1 was first identified by Dr. Jeffrey Sklar (Yale University) and coworkers as a chromosomal translocation partner in a rare subset of human T-ALLs carrying a t(7;9) translocation. Notch moved from a bit player to center stage when Drs. Jon Aster (Brigham & Women’s Hospital), A. Thomas Look (Dana-Farber Cancer Institute), and colleagues identified Notch1 activating mutations in the majority of human T-ALLs. These mutations occur in the Notch extracellular domain in the heterodimerization domain, allowing for ligand-independent signaling (HD mutations), or in the C-terminal PEST domain (PEST mutations), which increases Notch protein stability. In retrospect, the frequent association of Notch mutations with human T-ALL may have been predicted given that Notch is a potent T cell oncogene in mice. Notch-induced T-ALL shares many features with human T-ALL, suggesting that oncogenic Notch signaling may have similar functions in T cell tumorigenesis in mice and people. Notch functions as a T cell oncogene in both retroviral and transgenic models, where it is introduced as the primary oncogenic event, as well as in models where it is likely acquired as a collaborating event. Notch1 PEST mutations are frequent in the latter. Acquired Notch mutations in both humans and mouse T-ALL have only been identified in Notch1, whereas ectopic expression of the intracellular domain of Notch1, 2, and 3 all give rise to T cell neoplasms in mice. These differences may be related to variation in signal strength between these different Notch family members. Although intracellular Notch1 (Notch1-IC) is a potent inducer of T-ALL in retroviral and transgenic mouse models, this form of Notch is rarely present in human T-ALL. We recently assayed more commonly mutated Notch1 alleles in the retroviral model and found that HD, PEST, and HD + PEST mutations were weak inducers of T-ALL. When assayed on a background that predisposes to T-ALL, such as oncogenic ras, these weakly leukemogenic alleles shortened disease latency and gave rise to cell lines that were Notch-dependent. These data suggest that the common Notch mutations found in human T-ALL are weak tumor initiators but still give rise to tumors that are “addicted” to Notch. This strengthens the rationale for inhibiting Notch in T-ALL. The mouse also appears to be a useful model for testing Notch-targeted therapeutics, as the murine tumors are frequently susceptible to Notch inhibition, and mice exhibit some of the same toxicities as people when exposed to continuous Notch inhibition. A challenge for the field is to identify a safe therapeutic index for Notch inhibition. As a transcriptional regulator, an area of active investigation is identifying oncogenic Notch1 transcriptional targets. Several targets have been identified in both mouse and human, such as c-myc and regulators of T cell identify. Ongoing studies will likely reveal additional transcriptional targets, which is important for understanding the function of Notch in the pathogenesis of T-ALL.
34
Canté-Barrett, Kirsten, Laurent Holtzer, Henk van Ooijen, Rico Hagelaar, Valentina Cordo', Wim Verhaegh, Anja van de Stolpe, and Jules P. P. Meijerink. "A Test to Quantify NOTCH Pathway Activity in T Cell Acute Lymphoblastic Leukemia Patients." Blood 134, Supplement_1 (November 13, 2019): 4661. http://dx.doi.org/10.1182/blood-2019-122856.
Повний текст джерелаАнотація:
Background The NOTCH signaling pathway is pivotal for various physiological processes including immune responses, and has been implicated in the pathogenesis in many diseases including T-cell acute lymphoblastic leukemia (T-ALL). Over 70% of T-ALL patient samples contain mutations in NOTCH1 and/or FBXW7 that result in the activation of the NOTCH pathway. Various targeted drugs are available that inhibit NOTCH signaling, but their effectiveness varies due to variable NOTCH pathway activities among individual patients. Moreover, patients' leukemic cells that lack these mutations may still require NOTCH signaling. A quick and robust quantification of NOTCH pathway activity in primary patient samples would identify patients who could benefit from NOTCH targeted treatment. Aims In primary human T-ALL samples, we aimed to determine the NOTCH pathway activity in relation to active, intracellular NOTCH1 (ICN1) levels and in relation to NOTCH1 and/or FBXW7 mutations. Additionally, we investigated whether the NOTCH pathway activity score is more accurate than a mutation-based activity prediction. Methods Our test to assess functional NOTCH pathway activity in various cell types was applied to primary human T-ALL samples. The NOTCH test infers a quantitative NOTCH pathway activity score from mRNA levels of conserved direct NOTCH target genes based on a Bayesian network model. This model describes the causal relation between up- or downregulation of NOTCH target genes and the presence of an active or inactive NOTCH transcription complex. The Bayesian model was calibrated on publically available Affymetrix U133 Plus2.0 microarray datasets of samples with an active or inactive NOTCH pathway. Following validation on multiple cell types and malignancies, we scored NOTCH pathway activation in our well-characterized cohort of 117 T-ALL patient samples and related it to clinical and biological parameters including outcome. Results The NOTCH pathway model was calibrated using a microarray dataset containing high-grade serous ovarian cancer-which has high NOTCH activity-and normal ovarian tissue samples that lack NOTCH activity. Validation of the test using datasets from primary cells and cell lines of various origins revealed that it measures the NOTCH activity status in different cellular contexts. In primary diagnostic T-ALL samples, we observed a significant relationship between NOTCH pathway activity scores and active, intracellular cleaved NOTCH1 (ICN1) protein levels and the presence of NOTCH1-activating mutations. We next scored NOTCH pathway activity over the four T-ALL subgroups ETP-ALL, TLX, Proliferative and TALLMO. The TLX subgroup had the highest NOTCH activity levels compared to the other subgroups, consistent with the high percentage of TLX cases with NOTCH1/FBXW7 mutations. Strikingly, the significance of the correlation between ICN1 levels and NOTCH pathway activity was mainly attributed to the strong NOTCH1-activating mutations that include NOTCH1 juxtamembrane domain mutations, or hetero-dimerization mutations combined with PEST domain or FBXW7 mutations. When assessing the event-free survival and relapse-free survival curves, we observed that patients with the lowest (lower than the 25th-percentile) NOTCH pathway activity scores had the shortest event-free survival compared to the others (p<0.05, log-rank test). Summary/Conclusion High NOTCH pathway activation was mostly present in-but not limited to-T-ALL samples harboring strong NOTCH1 mutations, indicating that additional mechanisms can activate NOTCH signaling. Combined with the observation that the measured NOTCH pathway activity relates to ICN1 protein levels, this indicates that the pathway activity score more accurately reflects NOTCH pathway activity than the predicted activity based on NOTCH1 mutations alone. Disclosures Holtzer: Philips Research: Employment. Verhaegh:Philips Research: Employment. van de Stolpe:The Netherlands: Employment; Eindhoven: Employment; Philips Research: Employment.
35
Kong, Guangyao, Yuan-I. Chang, Erik A. Ranheim, Yun Zhou, Yangang Liu, Paul Lambert, Lan Zhou, Pamela Stanley, Warren S. Pear, and Jing Zhang. "Downregulating Notch Signaling in KrasG12D/+ Mice Inhibits Both T-Cell Leukemia and Myeloproliferative Neoplasm in a Cell-Autonomous Manner." Blood 124, no. 21 (December 6, 2014): 261. http://dx.doi.org/10.1182/blood.v124.21.261.261.
Повний текст джерелаАнотація:
Abstract Notch signaling is implicated in diverse functions in hematopoiesis, including stem cell maintenance, cell fate specification, cell proliferation, and apoptosis. Aberrant Notch signaling is associated with the pathogenesis of various hematopoietic malignancies. NOTCH1 mutations that lead to elevated intracellular Notch1 activity are identified in 50-60% of patients with acute T-cell lymphoblastic leukemia/lymphoma (T-ALL) and in 100% of oncogenic Ras-induced T-ALL in mice. Although Notch1 mutations contribute to the malignant transformation of normal T-cells to T-cell leukemia/lymphoma initiating cells in the KrasG12D/+-induced T-ALL model, it remains unclear whether Notch1 signaling is necessary for T-ALL genesis. Moreover, it remains controversial whether loss of Notch signaling promotes myeloproliferative neoplasms (MPN) in a cell-autonomous manner. To address these questions, we used genetic approaches to downregulate Notch signaling in KrasG12D/+ mice, which develop both T-ALL and MPN. Downregulation of Notch signaling in hematopoietic cells is achieved through Mx1-Cre–mediated conditional expression of Rosa26-GFP-dnMAML1, which inhibits canonical Notch signaling, or conditional knockout of Pofut1, which catalyzes O-fucosylation of Notch receptors and modulates Notch receptor ligand interactions. We found that either overexpression of dnMAML1 or deletion of Pofut1 significantly enhanced MPN phenotypes and shortened the survival of KrasG12D/+ mice. However, several pieces of evidence suggest that downregulation of Notch signaling in non-hematopoietic cells might influence MPN development. First, 100% of compound mice developed atopic dermatitis-like disease that is shown to promote MPN in a cell non-autonomous manner. Second, ~30% of endothelial cells were GFP-positive (expressing dnMAML1) in KrasG12D/+; Rosa26GFP-dnMAML1/+ mice. To determine whether downregulating Notch signaling prevents T-ALL and/or promotes MPN in a cell-autonomous manner, we transplanted the same number of KrasG12D/+, KrasG12D/+; Rosa26GFP-dnMAML1/+, or KrasG12D/+; Pofut1-/- bone marrow cells (CD45.2+) along with congeneic competitor cells (CD45.1+) into lethally irradiated mice (CD45.1+). As expected, inhibiting Notch signaling significantly blocked T-cell development and completely prevented T-ALL development in recipients; T-ALL that developed in a fraction of recipient mice were derived from rare donor cells that expressed oncogenic Kras and preserved intact Notch signaling. Surprisingly, we found that the percentage of donor-derived myeloid cells was significantly lower in recipients transplanted with KrasG12D/+; Rosa26GFP-dnMAML1/+ or KrasG12D/+; Pofut1-/- bone marrow cells and consequently none of them developed donor-derived MPN-like disease. In contrast, ~20% of the recipient mice transplanted with KrasG12D/+ cells developed a lethal, donor-derived MPN (P=0.02). Because the hematopoietic stem cell (HSC) frequency was significantly lower in KrasG12D/+; Rosa26GFP-dnMAML1/+ bone marrow than that in KrasG12D/+ bone marrow, we investigated whether the absence of the MPN was due to the reduced HSC reconstitution in recipients. To normalize for HSC numbers, we transplanted lethally irradiated mice with same number of KrasG12D/+ or KrasG12D/+; Rosa26GFP-dnMAML1/+ splenocytes, which contained similar numbers of HSCs mobilized from the bone marrow. Consistent with our previous observation, only 1 out of 12 recipient mice with KrasG12D/+; Rosa26GFP-dnMAML1/+ cells developed a donor-derived (KrasG12D/+; Rosa26GFP-dnMAML1/+) MPN disease, while 6 out of 12 recipient mice with KrasG12D/+ cells died with donor-derived MPN (P=0.02). Together, our results indicate that blocking Notch signaling inhibits both T-ALL and MPN development in a cell-autonomous manner. We are currently working on the underlying mechnisms. Disclosures No relevant conflicts of interest to declare.
36
Bellavia, Diana, Rocco Palermo, Maria Pia Felli, Isabella Screpanti, and Saula Checquolo. "Notch signaling as a therapeutic target for acute lymphoblastic leukemia." Expert Opinion on Therapeutic Targets 22, no. 4 (March 21, 2018): 331–42. http://dx.doi.org/10.1080/14728222.2018.1451840.
Повний текст джерела
37
Mansour, Marc R. "A role for aberrant Notch signaling in acute myeloid leukemia?" Leukemia & Lymphoma 47, no. 11 (January 2006): 2280–81. http://dx.doi.org/10.1080/10428190600908109.
Повний текст джерела
38
Lobry, Camille, Philmo Oh, and Iannis Aifantis. "Oncogenic and tumor suppressor functions of Notch in cancer: it’s NOTCH what you think." Journal of Experimental Medicine 208, no. 10 (September 26, 2011): 1931–35. http://dx.doi.org/10.1084/jem.20111855.
Повний текст джерелаАнотація:
Notch signaling is often considered a model hematopoietic proto-oncogene because of its role as the main trigger of T cell acute lymphoblastic leukemia (T-ALL). Although its role in T-ALL is well characterized and further supported by a high frequency of activating NOTCH1 mutations in T-ALL patients, it still remains an open question whether the effects of Notch signaling are causative in other types of cancer, including solid tumors. Growing evidence supported by recent studies unexpectedly shows that Notch signaling can also have a potent tumor suppressor function in both solid tumors and hematological malignancies. We discuss the intriguing possibility that the pleiotropic functions of Notch can be tumor suppressive or oncogenic depending on the cellular context.
39
Citarella, Anna, Giuseppina Catanzaro, Zein Mersini Besharat, Sofia Trocchianesi, Federica Barbagallo, Giorgio Gosti, Marco Leonetti, et al. "Hedgehog-GLI and Notch Pathways Sustain Chemoresistance and Invasiveness in Colorectal Cancer and Their Inhibition Restores Chemotherapy Efficacy." Cancers 15, no. 5 (February 25, 2023): 1471. http://dx.doi.org/10.3390/cancers15051471.
Повний текст джерелаАнотація:
Colorectal cancer (CRC) is a leading cause of cancer-related mortality and chemoresistance is a major medical issue. The epithelial-to-mesenchymal transition (EMT) is the primary step in the emergence of the invasive phenotype and the Hedgehog-GLI (HH-GLI) and NOTCH signaling pathways are associated with poor prognosis and EMT in CRC. CRC cell lines harboring KRAS or BRAF mutations, grown as monolayers and organoids, were treated with the chemotherapeutic agent 5-Fluorouracil (5-FU) alone or combined with HH-GLI and NOTCH pathway inhibitors GANT61 and DAPT, or arsenic trioxide (ATO) to inhibit both pathways. Treatment with 5-FU led to the activation of HH-GLI and NOTCH pathways in both models. In KRAS mutant CRC, HH-GLI and NOTCH signaling activation co-operate to enhance chemoresistance and cell motility, while in BRAF mutant CRC, the HH-GLI pathway drives the chemoresistant and motile phenotype. We then showed that 5-FU promotes the mesenchymal and thus invasive phenotype in KRAS and BRAF mutant organoids and that chemosensitivity could be restored by targeting the HH-GLI pathway in BRAF mutant CRC or both HH-GLI and NOTCH pathways in KRAS mutant CRC. We suggest that in KRAS-driven CRC, the FDA-approved ATO acts as a chemotherapeutic sensitizer, whereas GANT61 is a promising chemotherapeutic sensitizer in BRAF-driven CRC.
40
Xiu, Yan, Qianze Dong, Lin Fu, Aaron Bossler, Xiaobing Tang, Brendan Boyce, Nicholas Borcherding та ін. "Coactivation of NF-κB and Notch signaling is sufficient to induce B-cell transformation and enables B-myeloid conversion". Blood 135, № 2 (9 січня 2020): 108–20. http://dx.doi.org/10.1182/blood.2019001438.
Повний текст джерелаАнотація:
Abstract NF-κB and Notch signaling can be simultaneously activated in a variety of B-cell lymphomas. Patients with B-cell lymphoma occasionally develop clonally related myeloid tumors with poor prognosis. Whether concurrent activation of both pathways is sufficient to induce B-cell transformation and whether the signaling initiates B-myeloid conversion in a pathological context are largely unknown. Here, we provide genetic evidence that concurrent activation of NF-κB and Notch signaling in committed B cells is sufficient to induce B-cell lymphomatous transformation and primes common progenitor cells to convert to myeloid lineage through dedifferentiation, not transdifferentiation. Intriguingly, the converted myeloid cells can further transform, albeit at low frequency, into myeloid leukemia. Mechanistically, coactivation of NF-κB and Notch signaling endows committed B cells with the ability to self renew. Downregulation of BACH2, a lymphoma and myeloid gene suppressor, but not upregulation of CEBPα and/or downregulation of B-cell transcription factors, is an early event in both B-cell transformation and myeloid conversion. Interestingly, a DNA hypomethylating drug not only effectively eliminated the converted myeloid leukemia cells, but also restored the expression of green fluorescent protein, which had been lost in converted myeloid leukemia cells. Collectively, our results suggest that targeting NF-κB and Notch signaling will not only improve lymphoma treatment, but also prevent the lymphoma-to-myeloid tumor conversion. Importantly, DNA hypomethylating drugs might efficiently treat these converted myeloid neoplasms.
41
Chan, Steven M., Andrew P. Weng, Robert Tibshirani, Jon C. Aster, and Paul J. Utz. "Notch signals positively regulate activity of the mTOR pathway in T-cell acute lymphoblastic leukemia." Blood 110, no. 1 (July 1, 2007): 278–86. http://dx.doi.org/10.1182/blood-2006-08-039883.
Повний текст джерелаАнотація:
Constitutive Notch activation is required for the proliferation of a subgroup of T-cell acute lymphoblastic leukemia (T-ALL). Downstream pathways that transmit pro-oncogenic signals are not well characterized. To identify these pathways, protein microarrays were used to profile the phosphorylation state of 108 epitopes on 82 distinct signaling proteins in a panel of 13 T-cell leukemia cell lines treated with a gamma-secretase inhibitor (GSI) to inhibit Notch signals. The microarray screen detected GSI-induced hypophosphorylation of multiple signaling proteins in the mTOR pathway. This effect was rescued by expression of the intracellular domain of Notch and mimicked by dominant negative MAML1, confirming Notch specificity. Withdrawal of Notch signals prevented stimulation of the mTOR pathway by mitogenic factors. These findings collectively suggest that the mTOR pathway is positively regulated by Notch in T-ALL cells. The effect of GSI on the mTOR pathway was independent of changes in phosphatidylinositol-3 kinase and Akt activity, but was rescued by expression of c-Myc, a direct transcriptional target of Notch, implicating c-Myc as an intermediary between Notch and mTOR. T-ALL cell growth was suppressed in a highly synergistic manner by simultaneous treatment with the mTOR inhibitor rapamycin and GSI, which represents a rational drug combination for treating this aggressive human malignancy.
42
Palomero, Teresa, Duncan T. Odom, Adam Margolin, Jon Aster, Andrea Califano, Richard A. Young, A. Thomas Look, and Adolfo A. Ferrando. "Transcriptional Regulatory Networks Downstream of NOTCH1 in T-Cell Acute Lymphoblastic Leukemia." Blood 106, no. 11 (November 16, 2005): 740. http://dx.doi.org/10.1182/blood.v106.11.740.740.
Повний текст джерелаАнотація:
Abstract The NOTCH1 signaling pathway plays a critical role in the regulation of hematopoietic stem cell homeostasis and is required for lymphocytes to adopt a T-cell fate. Importantly, aberrant activation of NOTCH signaling due to activating mutations in the NOTCH1 gene is involved in the pathogenesis of over 50% human T-cell acute lymphoblastic leukemias (T-ALL) and the therapeutic efficacy of inhibition of NOTCH signaling via gamma-secretase inhibitors (GSI) is currently being tested in clinical trials. However, little is known about the transcriptional programs activated downstream of NOTCH1 activation that contribute to the transformation of T-cell progenitors. Here we used chromatin immunoprecipitation and promoter microarrays (ChIP-on-chip) to identify direct transcriptional targets of NOTCH1; and microarray gene expression analysis to decipher the oncogenic transcriptional network activated by the NOTCH1 oncoprotein in T-ALL cells. Using the Hu19K arrays that contain over 13,000 human promoter regions, we have identified 134 candidate direct targets (p<0.0001) of NOTCH1 in the HPB-ALL T-ALL cell line by ChIP-on-chip. NOTCH1 targets identified by ChIP -on-chip included known direct targets of NOTCH1 such as preTCRA, as well as genes involved in T-cell signaling (CD3D, ASE-1/CD3E associated protein), proliferation (CDK5, CDC25A, RBL1, BUB3 and ING3) and survival (Survivin). Inhibition of NOTCH1 signaling with compound E, a strong GSI, induced a gene expression signature characterized by the downregulation of known NOTCH1 direct target genes such as DELTEX1, HES1 and HEY1. Analysis of different cell lines representative of different stages of maturation arrest and different oncogenic groups of T-ALL identified a core signature of transcriptional responses to NOTCH signaling inhibition, which included the downregulation of the MYC oncogene as well as numerous genes involved in nucleotide metabolism and protein synthesis. In addition, cell cycle inhibitors p27/KIP1 and p18/INK4D were upregulated. Importantly, 13 of the top direct target genes of NOTCH1 identified by ChIP-on-chip were consistently downregulated (p<0.005) upon NOTCH signaling inhibition in multiple cell lines. However, more restricted responses to NOTCH1 signaling inhibition, which included important developmental regulators of T-cell development such as the pre-TCRA, were present in specific groups of samples. These results demonstrate that NOTCH1 activation induces a complex transcriptional response in T-ALL cells, which is in part dependent on the stage of T-cell development and/or the interaction with other T-ALL transcription factor oncogenes. Common effector pathways downstream of NOTCH signaling may represent novel therapeutic targets for the treatment of T-ALL, while cell type specific responses may influence the cellular effects and the clinical efficacy of NOTCH signaling inhibitors currently under evaluation in clinical trials. Overall, our results indicate that NOTCH1 acts as a master transcriptional regulator at the top of a complex regulatory network that contributes to leukemogenesis by regulating multiple critical pathways involved in the regulation of T-cell differentiation, proliferation and survival.
43
Fragoso, Ana Rita, Tin Mao, Song Wang, Steven Schaffert, Hyeyoung Min, Warren S. Pear, and Chang-Zheng Chen. "Essential Role for Mir-181a1/b1 In T-Cell Acute Lymphoblastic Leukemia." Blood 116, no. 21 (November 19, 2010): 470. http://dx.doi.org/10.1182/blood.v116.21.470.470.
Повний текст джерелаАнотація:
Abstract Abstract 470 MiRNA-mediated gene regulation represents a fundamental layer of post-transcriptional control of gene expression with diverse functional roles in normal development and tumorigenesis. Whereas some studies have shown that over-expression of miRNA genes may contribute to cancer development and progression, it is yet to be rigorously tested by the loss-of-function genetic approaches whether miRNA genes are required for cancer development and maintenance in mice. Here we show that mir-181a1/b1 coordinates Notch and pre-TCR signals during normal thymocyte differentiation and plays an essential role in development and onset of T-cell acute lymphoblastic leukemia (T-ALL) induced by some Notch mutations. Using gain-of-function and loss-of-function approaches, we demonstrated that mir-181a1/b1 controls Notch and pre-TCR receptor signals during the early stages of T cell development in the thymus by repressing multiple negative regulators of both pathways, including Nrarp, PTPN-22, SHP2, DUSP5, and DUSP6. These results illustrate that a single miRNA can coordinate multiple signaling pathways by modulating the timing and strength of signaling at different stages. Intriguingly, synergistic signaling between Notch and pre-TCR pathways is necessary for the development of T-ALL, and miR-181 family miRNAs are aberrantly expressed in T-ALL patients. These observations raise the possibility that mir-181a1/b1 might contribute to the onset or maintenance of T-ALL by targeting similar pathways in tumor cells as it does in normal thymic progenitor cells. In support of this notion, we found that loss of mir-181a1/b1 significantly delayed the onset and development of T-ALL induced by intracellular domain of Notch1 (ICN1) and caused a 32% increase in the median survival time from 41 days to 54 days in T-ALL mice. Importantly, we noted that loss of mir-181a1/b1 more efficiently repressed the leukemogeneic potential of cells with lower levels of ICN1 expression, suggesting that mir-181a1/b1 may be more effective in inhibiting T-ALL development induced by a Notch mutant with weaker signal strength. Indeed, we demonstrated that loss of mir-181a1b1 essentially blocked T-ALL development induced by the weaker Notch mutant and dramatically decreased mortality from 60% to 10% in these T-ALL mice. Since human Notch mutations identified in T-ALL patients generally have weaker signaling strength and lower oncogenic potential than that of ICN1, our findings indicate that mir-181a1/b1 may play an essential role in development of normal thymic progenitors and Notch-induced T-ALL and may be targeted to treat T-ALL patients harboring Notch mutations. Disclosures: No relevant conflicts of interest to declare.
44
Okuhashi, Yuki, Mai Itoh, Nobuo Nara, and Shuji Tohda. "Effects of NOTCH Knockdown on the Proliferation and mTOR Signaling of T-ALL and AML Cell Lines." Blood 122, no. 21 (November 15, 2013): 1396. http://dx.doi.org/10.1182/blood.v122.21.1396.1396.
Повний текст джерелаАнотація:
Abstract Background The activation of Notch is crucial for the growth of T-ALL cells with NOTCH1 mutations. The precise roles of Notch signaling in AML cells are not fully understood, although the growth of AML cells is diversely affected by Notch ligand stimulation as we previously reported. We also reported the effects of γ-secretase inhibitors (GSIs), which block Notch activation, on the growth of leukemia cells. However, these effects might not necessarily be due to Notch inhibition as GSIs also exhibit some off-target effects. To elucidate the roles of Notch signaling in leukemia cells, we examined the effects of small interfering RNA (siRNA)-mediated knockdown of NOTCH1 and NOTCH2on cell proliferation and down-stream signaling pathways such as mTOR signaling in T-ALL and AML cell lines. Methods Two T-ALL cell lines (DND-41 and KOPT-K1) and 2 AML cell lines (THP-1 and TMD7) were used in this study. The cells were transfected with siRNAs targeting NOTCH1 (siN1), NOTCH2 (siN2), or control siRNA by using the pipette tip chamber-based electroporation system. The effects of siN1 and siN2 transfection on cell proliferation and induction of apoptosis were examined using a colorimetric WST-8 assay and by observing cytospin preparations of the harvested cells, respectively. The effects of the siRNA-transfection on the mRNA and protein expression were examined by quantitative RT-PCR and immunoblotting, respectively. Results Transfection with siN1 and siN2 selectively suppressed the expression of Notch1 and Notch2 mRNA and protein, respectively. In T-ALL cell lines, NOTCH1 knockdown as well as NOTCH2 knockdown suppressed cell proliferation and induced apoptosis. Immunoblot analysis showed that Myc expression was downregulated in NOTCH1-knockdown cells but not affected in NOTCH2-knockdown cells. In AML cell lines, cell proliferation was not significantly affected by NOTCH siRNAs. NOTCH2 knockdown increased the level of cleaved Notch1 fragment without increasing Notch1 expression. The knockdown of NOTCH1 and NOTCH2 reduced the expression and phosphorylation of mTOR protein in THP-1 cells. To confirm this finding, we examined the effects of activation of Notch by the recombinant Notch ligands, Jagged1 and Delta1, on the expression of mTOR protein. The activation of Notch resulted in an increase in the level of the mTOR protein and its phosphorylation in THP-1 cells. Thus, siRNA-transfection and ligand stimulation of Notch showed contrasting effects. Phosphorylation of Akt, 4E-BP1, and S6K was also induced after the stimulation. Discussion Using siRNA-mediated knockdown experiments, we found that Notch2 signaling plays a role in the growth of T-ALL cells, independent of Myc expression. The autonomous activation of Notch signaling in AML cells had little effect on the proliferation of these cells. Notch2 protein seemed to be involved in the activation of Notch1 in AML cells. Regarding the crosstalk between Notch and mTOR signaling, it is known that the Notch-induced Hes1 protein suppresses PTEN transcription, resulting in the promotion of Akt phosphorylation. We found an alternative pathway linking Notch and mTOR signaling in THP-1 cells in which the PTEN gene is homozygously deleted. In THP-1 cells, Notch activation promotes the expression and phosphorylation of the mTOR protein and the activation of mTOR signaling. These findings would contribute to the development of effective Notch-targeted therapy against leukemia. Disclosures: No relevant conflicts of interest to declare.
45
Kuang, Shaoqing, Patrick Zweidler-McKay, Hui Yang, Zhi Hong Fang, Weigang Tong, and Guillermo Garcia-Manero. "Epigenetic Inactivation of Notch Signaling Target Genes HES in B Cell Acute Lymphoblastic Leukemia." Blood 112, no. 11 (November 16, 2008): 3372. http://dx.doi.org/10.1182/blood.v112.11.3372.3372.
Повний текст джерелаАнотація:
Abstract The Notch signaling pathway has been implicated in multiple functions during normal hemato-lymphoid development. It also plays critical roles in T-cell leukemogenesis through influencing T-cell proliferation, differentiation and survival. In contrast, we have previously reported a tumor suppressor role in B-cell leukemias, where Notch signaling leads to growth inhibition and apoptosis. The Notch target genes Hairy/Enhancer of Split (HES1-7) encode transcriptional repressors with basic helix-loop-helix (bHLH) domains. Functional and phenotypic analyses of some of the HES family members have been reported, however, expression and epigenetic regulation of the HES family in leukemia is largely unknown. Using Methylated CpG Island Amplification (MCA) / DNA promoter microarray, we identified several HES family genes as hypermethylated in B cell acute lymphoblastic leukemia (B ALL). We further investigated the comprehensive methylation profiles of HES family genes in a panel of leukemia cell lines and ALL patient samples by bisulfite pyrosequencing. Aberrant DNA methylation of HES2, HES4, HES5 and HES6 was detected in most B ALL cell lines including B-JAB, RS4:11, REH, Raji and Ramos but not in normal B cell controls. In contrast, in T cell leukemia cell lines such as Molt4, PEER, T-ALL1 and J-TAG, these genes were generally unmethylated. In B ALL patient samples, the frequencies of DNA methylation in the promoter regions of these genes were 25% for HES2, 50% for HES4, 76% for HES5 and 71% for HES6. Expression analysis of HES4, HES5 and HES6 in leukemia cell lines by real-time PCR further confirmed methylation associated gene silencing. Treatment of methylated/silenced cell lines with DNA methyltransferase inhibitor 5’-aza-2’-deoxycytidine resulted in HES gene re-expression. Finally, forced re-expression of HES5 and HES6 in methylation silenced Rs4 and REH cell lines inhibited cell growth. These results suggest that the Notch/HES signaling pathway is epigenetically-inactivated in B ALL. These data support the role of the HES family as tumor suppressors in pre-B ALL and establish epigenetic modulation as a novel mechanism of Notch pathway regulation. We anticipate that therapies capable of activating Notch/HES signaling may have therapeutic potential in B cell leukemias.
46
Rodriguez-Rodriguez, Sonia, Lin Wang, Huajia Zhang, Amy Zollman, Angelo A. Cardoso, and Nadia Carlesso. "SKP2 Is Dispensable for Normal T-Cell Development but Required for T-Cell Leukemogenesis." Blood 124, no. 21 (December 6, 2014): 2214. http://dx.doi.org/10.1182/blood.v124.21.2214.2214.
Повний текст джерелаАнотація:
Abstract Acute Lymphoblastic Leukemia (ALL) is the most common pediatric cancer. Despite the significant clinical successes in the treatment of pediatric T-ALL, leukemia relapse, refractory disease and induction failure (around 30% of patients) remain significant clinical problems, which are often life-threatening. ALL remains the second leading cause of childhood death. Thus, more effective, curative therapeutic strategies are much needed, particularly for refractory and relapse T- ALL. Recent advances in understanding the biology and the molecular alterations of acute lymphoblastic leukemias have led to identification of new molecular targets, such as the Notch signaling pathway. Constitutive activation of Notch signaling is involved in more than 50% of human T-ALL, and overexpression of activated Notch induces T-cell leukemia and lymphoma in murine tumor models. However, disruption of Notch signaling by gamma-secretase inhibitors (GSI) failed to fulfill its clinical promise and, overall, the significant advances attained in dissecting the molecular effectors in T-ALL has yet to translate into effective, curative molecular therapies for relapse patients. Furthermore, despite multiple studies on Notch signaling, little is known on the role of its downstream mediators in T-cell ALL. Previous studies in our laboratory demonstrated that Notch1 activation induces transcriptional activation of SKP2, the F-box protein of the SCF E3-ubiquitin ligase complex. SKP2 is the main F-box protein regulating cell cycle, promoting downregulation of the CKIs (p21Cip1, p27Kip1, p57Kip2 and p130) and its overexpression accelerate cell cycle progression in hematopoietic cells. SKP2 overexpression is frequently associated with cancers, in particular lymphomas and leukemias, and correlates with poor prognosis. We found that Skp2 expression is dynamically regulated during T-cell development coinciding with the Notch expression pattern. Moreover, primary thymocytes cultured in vitro, responded to Notch stimulation by the Delta1 ligand increasing their Skp2 expression and their cell cycle status, whereas the loss of SKP2 impaired their ability to mount a proliferative response to IL-7 stimulation. Importantly, we observed that SKP2 expression is increased in T-ALL patient samples and that mice with Notch-induced T-cell leukemia showed 5 fold upregulation of Skp2 expression. Our hypotheses are that Notch activation promotes T-cell leukemogenesis by altering the cell cycle control through upregulation of Skp2, and that selective targeting of SKP2 is a novel, effective therapeutic strategy for childhood T-ALL. To test whether SKP2 is a key downstream mediator of Notch in T-ALL, we transduced oncogenic Notch (ICN; the constitutive intracellular form) in hematopoietic cells lacking SKP2 from Skp2-/- null mice, and in controls and we determine their ability to induce leukemia in irradiated recipients. Loss of SKP2 significantly delayed the development of T-cell leukemia and increased animal survival by 40%. Taken together, these results demonstrate a previously unrecognized role for SKP2 in the initiation and progression of T-ALL and its potential role as a therapeutic target. Disclosures No relevant conflicts of interest to declare.
47
Joshi, Ila, Lisa M. Minter, Janice Telfer, Renée M. Demarest, Anthony J. Capobianco, Jon C. Aster, Piotr Sicinski, Abdul Fauq, Todd E. Golde, and Barbara A. Osborne. "Notch signaling mediates G1/S cell-cycle progression in T cells via cyclin D3 and its dependent kinases." Blood 113, no. 8 (February 19, 2009): 1689–98. http://dx.doi.org/10.1182/blood-2008-03-147967.
Повний текст джерелаАнотація:
Abstract Notch signaling plays a role in normal lymphocyte development and function. Activating Notch1-mutations, leading to aberrant downstream signaling, have been identified in human T-cell acute lymphoblastic leukemia (T-ALL). While this highlights the contribution of Notch signaling to T-ALL pathogenesis, the mechanisms by which Notch regulates proliferation and survival in normal and leukemic T cells are not fully understood. Our findings identify a role for Notch signaling in G1-S progression of cell cycle in T cells. Here we show that expression of the G1 proteins, cyclin D3, CDK4, and CDK6, is Notch-dependent both in vitro and in vivo, and we outline a possible mechanism for the regulated expression of cyclin D3 in activated T cells via CSL (CBF-1, mammals; suppressor of hairless, Drosophila melanogaster; Lag-1, Caenorhabditis elegans), as well as a noncanonical Notch signaling pathway. While cyclin D3 expression contributes to cell-cycle progression in Notch-dependent human T-ALL cell lines, ectopic expression of CDK4 or CDK6 together with cyclin D3 shows partial rescue from γ-secretase inhibitor (GSI)-induced G1 arrest in these cell lines. Importantly, cyclin D3 and CDK4 are highly overexpressed in Notch-dependent T-cell lymphomas, justifying the combined use of cell-cycle inhibitors and GSI in treating human T-cell malignancies.
48
Ohnuki, Hidetaka, Hirofumi Inoue, Nobuaki Takemori, Hironao Nakayama, Tomohisa Sakaue, Shinji Fukuda, Daisuke Miwa, et al. "BAZF, a novel component of cullin3-based E3 ligase complex, mediates VEGFR and Notch cross-signaling in angiogenesis." Blood 119, no. 11 (March 15, 2012): 2688–98. http://dx.doi.org/10.1182/blood-2011-03-345306.
Повний текст джерелаАнотація:
Abstract Angiogenic homeostasis is maintained by a balance between vascular endothelial growth factor (VEGF) and Notch signaling in endothelial cells (ECs). We screened for molecules that might mediate the coupling of VEGF signal transduction with down-regulation of Notch signaling, and identified B-cell chronic lymphocytic leukemia/lymphoma6-associated zinc finger protein (BAZF). BAZF was induced by VEGF-A in ECs to bind to the Notch signaling factor C-promoter binding factor 1 (CBF1), and to promote the degradation of CBF1 through polyubiquitination in a CBF1-cullin3 (CUL3) E3 ligase complex. BAZF disruption in vivo decreased endothelial tip cell number and filopodia protrusion, and markedly abrogated vascular plexus formation in the mouse retina, overlapping the retinal phenotype seen in response to Notch activation. Further, impaired angiogenesis and capillary remodeling were observed in skin-wounded BAZF−/− mice. We therefore propose that BAZF supports angiogenic sprouting via BAZF-CUL3-based polyubiquitination-dependent degradation of CBF1 to down-regulate Notch signaling.
49
Kato, Takayasu, Mamiko Sakata-Yanagimoto, Hidekazu Nishikii, Yasuyuki Miyake, Yasuhisa Yokoyama, Yukitugu Asabe, Naoshi Obara, Kazumi Suzukawa, Ryoichiro Kageyama, and Shigeru Chiba. "Hes1 Is Responsible For Notch Signaling-Mediated Suppression Of Acute Myeloid Leukemia Development Via Suppression Of FLT3 Expression." Blood 122, no. 21 (November 15, 2013): 3800. http://dx.doi.org/10.1182/blood.v122.21.3800.3800.
Повний текст джерелаАнотація:
Abstract Background The transcription factor Hairy enhancer of split1 (Hes1) is well characterized as a downstream target of Notch signaling. Hes1 is a basic helix-loop-helix-type protein, and represses target gene expression. Notch signaling has been proposed to play both pro- and anti-tumorigenic roles; it promotes development of T-cell acute lymphoblastic leukemia (T-ALL), while serves as a tumor suppressor for acute myeloid leukemia (AML). Hes1 has been proven as an essential mediator of Notch signaling in T-ALL development. In contrast, we reported, in the last annual meeting, that Hes1 functions as a tumor suppressor against AML development, using a mouse model of AML induced by the MLL-AF9 fusion protein. We further explored the mechanism of Hes1-mediated suppression of AML development. Methods Common myeloid progenitors (CMPs) purified from RBP-Jf/f mouse bone marrow (BM) were serially transduced with MLL-AF9 and Cre recombinase (iCre) using retroviral vectors, and transplanted into lethally irradiated syngenic mice. CMPs from Hes1-/- mouse fetal liver were also retrovirally transduced with MLL-AF9 and transplanted after multiple rounds of replating, and then, expression levels of downstream targets were evaluated by cDNA array. Next Hes1 was retrovirally re-expressed in MLL-AF9/Hes1-/- cells and these cells were transplanted. MLL-AF9-transduced cells were treated with a hamster anti-mouse Notch agonistic antibody (Notch Ab). Results Mice transplanted with MLL-AF9/RBP-J-/- cells developed leukemia at shorter latencies than those with MLL-AF9/RBPJ+/+ cells. MLL-AF9-transduced Hes1-/- cells formed the higher number of colonies at third replating compared with MLL-AF9-transduced Hes1+/+ cells. When infused into irradiated syngenic mice, MLL-AF9/Hes1-/- cells developed leukemia at shorter latencies than MLL-AF9/ Hes1+/+ cells (MLL-AF9/Hes1-/-, 7-10 weeks, n=18 vs MLL-AF9/Hes1+/+, 10-14 weeks, n=18; p<0.001). When Hes1 was retrovirally re-expressed in MLL-AF9/Hes1-/- cells, these cells developed leukemia in recipient mice at longer latencies than mock-transduced MLL-AF9/Hes1-/- cells (Hes1/MLL-AF9, 12 weeks, n=8 vs mock/MLL-AF9, 5-7 weeks, n=7 p<0.001). When treated with an anti-Notch2 Ab, MLL-AF9/Hes1+/+ cells underwent apoptosis, whereas MLL-AF9/Hes1-/- cells did not. These results indicate that Hes1 is a definitive downstream mediator for Notch signaling-mediated suppression of AML. Among the genes with different expression levels between MLL-AF9/Hes1-/- and MLL-AF9/Hes1+/+ leukemia cells, FMS-like tyrosine kinase 3 (FLT3) was expressed at significantly higher levels in MLL-AF9/Hes1-/- leukemia cells as well as RBP-J-null Background. It was also demonstrated that FLT3 and ERK were phosphorylated with FLT3 ligand stimulation in the MLL-AF9-immortalized cells specifically with the Hes1-/- Background. An FLT3 inhibitor efficiently abrogated the proliferation of MLL-AF9/Hes1-/- leukemia cells. We accessed the independent database containing mRNA expression profiles and found that the expression level of Flt3 mRNA was negatively correlated with those of Hes1 in AML samples. Conclusion Canonical Notch signaling serves as a tumor suppressor in MLL-AF9-induced AML through upregulation of Hes1. Hes1 is an essential Notch signaling mediator for AML suppression. At least a part of Hes1 function might be explained by repression of FLT3. Disclosures: No relevant conflicts of interest to declare.
50
Maillard, Ivan. "Notch Signaling in Graft-Versus-Host Disease." Blood 118, no. 21 (November 18, 2011): SCI—14—SCI—14. http://dx.doi.org/10.1182/blood.v118.21.sci-14.sci-14.
Повний текст джерелаАнотація:
Abstract SCI-14 Notch is a highly conserved signaling pathway with multiple functions in health and disease. In the hematopoietic system, Notch was first described for its essential role at early stages of T cell development in the thymus and for its involvement in T cell acute lymphoblastic leukemia. In addition, Notch is being increasingly recognized as a potent regulator of antigen-driven mature T cell responses with context-dependent effects. These effects are influenced by the regulated expression of Jagged and Delta-like Notch ligands in antigen-presenting cells under the control of Toll-like receptors and other innate signals. We are investigating the importance of the Notch pathway in T cell alloimmunity in the setting of allogeneic bone marrow or peripheral blood stem cell transplantation (allo-BMT). After allo-BMT, alloimmune T cell responses mediate beneficial graft-versus-tumor (GVT) activity as well as detrimental graft-versus-host disease (GVHD). Using the pan-Notch inhibitor DNMAML and other genetic models of Notch inhibition, we have discovered an essential function for Notch signaling in donor-derived alloreactive T cells. In multiple mouse models of allo-BMT, infusion of Notch-deficient T cells as compared to wild-type T cells led to dramatically reduced GVHD severity and lethality. This effect was apparent for both CD4+ and CD8+ T cells and did not involve global immunosuppression, since Notch-deficient T cells proliferated normally and expanded in host lymphohematopoietic organs. However, Notch-deficient donor T cells failed to accumulate in the gut, a key GVHD target organ, and produced markedly decreased amounts of the pro-inflammatory cytokines IFN-γ, TNF-α, and IL-2. In parallel, Notch inhibition was associated with increased accumulation of FoxP3+CD4+ T cells. Decreased cytokine production could not be explained by a classical T helper differentiation defect. In contrast to their defective induction of GVHD, Notch-deficient T cells remained capable of mediating cytotoxic and anti-tumor responses both in vitro and in vivo, leading to preserved GVT activity even against large numbers of tumor cells. We are currently investigating the molecular and cellular mechanisms of Notch action in alloreactive T cells. We are also exploring the role of individual Notch receptors and ligands at the alloimmune synapse in vivo. Altogether, our findings identify Notch inhibition in donor T cells as a novel strategy to induce beneficial immunomodulation rather than global immunosuppression after allo-BMT. Disclosures: No relevant conflicts of interest to declare.