Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2018

Open Access 01-12-2018 | Research

JAG1 overexpression contributes to Notch1 signaling and the migration of HTLV-1-transformed ATL cells

Authors: Marcia Bellon, Ramona Moles, Hassiba Chaib-Mezrag, Joanna Pancewicz, Christophe Nicot

Published in: Journal of Hematology & Oncology | Issue 1/2018

Login to get access

Abstract

Background

HTLV-1 is a retrovirus that infects over 20 million people worldwide and is responsible for the hematopoietic malignancy adult T cell leukemia (ATL). We previously demonstrated that Notch is constitutively activated in ATL cells. Activating genetic mutations were found in Notch; however, Notch signaling was also activated in the absence of genetic mutations suggesting the existence of other mechanisms.

Methods

We analyzed the expression of Notch receptor ligands in HTLV-I-transformed cells, ATL patient-derived cell lines, and fresh uncultured ATL samples by RT-PCR, FACS, and immunohistochemistry. We then investigated viral and cellular molecular mechanisms regulating expression of JAG1. Finally, using shRNA knock-down and neutralizing antibodies, we investigated the function of JAG1 in ATL cells.

Results

Here, we report the overexpression of the Notch ligand, JAG1, in freshly uncultured ATL patient samples compared to normal PBMCs. We found that in ATL cells, JAG1 overexpression relies upon the viral protein Tax and cellular miR-124a, STAT3, and NFATc1. Interestingly, our data show that blockade of JAG1 signaling dampens Notch1 downstream signaling and limits cell migration of transformed ATL cells.

Conclusions

Our results suggest that targeting JAG1 can block Notch1 activation in HTLV-I-transformed cells and represents a new target for immunotherapy in ATL patients.
Literature
1.
Purow B. Notch inhibition as a promising new approach to cancer therapy. Adv Exp Med Biol. 2012;727:305–19.CrossRef
2.
Cheng F, Pekkonen P, Ojala PM. Instigation of Notch signaling in the pathogenesis of Kaposi’s sarcoma-associated herpesvirus and other human tumor viruses. Future Microbiol. 2012;7(10):1191–205.CrossRef
3.
Arcaini L, Rossi D, Lucioni M, Nicola M, Bruscaggin A, Fiaccadori V, Riboni R, Ramponi A, Ferretti VV, Cresta S, et al. The NOTCH pathway is recurrently mutated in diffuse large B-cell lymphoma associated with hepatitis C virus infection. Haematologica. 2015;100(2):246–52.CrossRef
4.
Hofelmayr H, Strobl LJ, Marschall G, Bornkamm GW, Zimber-Strobl U. Activated Notch1 can transiently substitute for EBNA2 in the maintenance of proliferation of LMP1-expressing immortalized B cells. J Virol. 2001;75(5):2033–40.CrossRef
5.
Pancewicz J, Nicot C. Current views on the role of Notch signaling and the pathogenesis of human leukemia. BMC Cancer. 2011;11:502.CrossRef
6.
Chastagner P, Israel A, Brou C. AIP4/Itch regulates Notch receptor degradation in the absence of ligand. PLoS One. 2008;3(7):e2735.CrossRef
7.
Kandachar V, Roegiers F. Endocytosis and control of Notch signaling. Curr Opin Cell Biol. 2012;24(4):534–40.CrossRef
8.
Welcker M, Clurman BE. FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation. Nat Rev Cancer. 2008;8(2):83–93.CrossRef
9.
Nasr R, Marcais A, Hermine O, Bazarbachi A. Overview of targeted therapies for adult T-cell leukemia/lymphoma. Methods Mol Biol. 2017;1582:197–216.CrossRef
10.
Nicot C. HTLV-I Tax-mediated inactivation of cell cycle checkpoints and DNA repair pathways contribute to cellular transformation: “a random mutagenesis model”. J Cancer Sci. 2015;2(2).
11.
Bellon M, Baydoun HH, Yao Y, Nicot C. HTLV-I Tax-dependent and -independent events associated with immortalization of human primary T lymphocytes. Blood. 2010;115(12):2441–8.CrossRef
12.
Giam CZ, Semmes OJ. HTLV-1 infection and adult T-cell leukemia/lymphoma-a tale of two proteins: tax and HBZ. Viruses. 2016;8(6).CrossRef
13.
Pancewicz J, Taylor JM, Datta A, Baydoun HH, Waldmann TA, Hermine O, Nicot C. Notch signaling contributes to proliferation and tumor formation of human T-cell leukemia virus type 1-associated adult T-cell leukemia. Proc Natl Acad Sci U S A. 2010;107(38):16619–24.CrossRef
14.
Weng AP, Ferrando AA, Lee W, Morris JP, Silverman LB, Sanchez-Irizarry C, Blacklow SC, Look AT, Aster JC. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004;306(5694):269–71.CrossRef
15.
Lobry C, Oh P, Aifantis I. Oncogenic and tumor suppressor functions of Notch in cancer: it’s NOTCH what you think. J Exp Med. 2011;208(10):1931–5.CrossRef
16.
Bellon M, Lu L, Nicot C. Constitutive activation of Pim1 kinase is a therapeutic target for adult T-cell leukemia. Blood. 2016;127(20):2439–50.CrossRef
17.
Chevalier SA, Durand S, Dasgupta A, Radonovich M, Cimarelli A, Brady JN, Mahieux R, Pise-Masison CA. The transcription profile of Tax-3 is more similar to Tax-1 than Tax-2: insights into HTLV-3 potential leukemogenic properties. PLoS One. 2012;7(7):e41003.CrossRef
18.
Gasparian AV, Yao YJ, Kowalczyk D, Lyakh LA, Karseladze A, Slaga TJ, Budunova IV. The role of IKK in constitutive activation of NF-kappaB transcription factor in prostate carcinoma cells. J Cell Sci. 2002;115(Pt 1):141–51.
19.
Hoesel B, Schmid JA. The complexity of NF-kappaB signaling in inflammation and cancer. Mol Cancer. 2013;12:86.CrossRef
20.
Billman MR, Rueda D, Bangham CRM. Single-cell heterogeneity and cell-cycle-related viral gene bursts in the human leukaemia virus HTLV-1. Wellcome Open Res. 2017;2:87.CrossRef
21.
Takeda S, Maeda M, Morikawa S, Taniguchi Y, Yasunaga J, Nosaka K, Tanaka Y, Matsuoka M. Genetic and epigenetic inactivation of tax gene in adult T-cell leukemia cells. Int J Cancer. 2004;109(4):559–67.CrossRef
22.
Yeh CH, Moles R, Nicot C. Clinical significance of microRNAs in chronic and acute human leukemia. Mol Cancer. 2016;15(1):37.CrossRef
23.
Akerblom M, Sachdeva R, Barde I, Verp S, Gentner B, Trono D, Jakobsson J. MicroRNA-124 is a subventricular zone neuronal fate determinant. J Neurosci. 2012;32(26):8879–89.CrossRef
24.
Pan MG, Xiong Y, Chen F. NFAT gene family in inflammation and cancer. Curr Mol Med. 2013;13(4):543–54.CrossRef
25.
Chang WH, Ho BC, Hsiao YJ, Chen JS, Yeh CH, Chen HY, Chang GC, Su KY, Yu SL. JAG1 is associated with poor survival through inducing metastasis in lung cancer. PLoS One. 2016;11(3):e0150355.CrossRef
26.
Pedrosa AR, Trindade A, Fernandes AC, Carvalho C, Gigante J, Tavares AT, Dieguez-Hurtado R, Yagita H, Adams RH, Duarte A. Endothelial Jagged1 antagonizes Dll4 regulation of endothelial branching and promotes vascular maturation downstream of Dll4/Notch1. Arterioscler Thromb Vasc Biol. 2015;35(5):1134–46.CrossRef
27.
Choi K, Ahn YH, Gibbons DL, Tran HT, Creighton CJ, Girard L, Minna JD, Qin FX, Kurie JM. Distinct biological roles for the notch ligands Jagged-1 and Jagged-2. J Biol Chem. 2009;284(26):17766–74.CrossRef
28.
Jundt F, Probsting KS, Anagnostopoulos I, Muehlinghaus G, Chatterjee M, Mathas S, Bargou RC, Manz R, Stein H, Dorken B. Jagged1-induced Notch signaling drives proliferation of multiple myeloma cells. Blood. 2004;103(9):3511–5.CrossRef
29.
Li D, Masiero M, Banham AH, Harris AL. The notch ligand JAGGED1 as a target for anti-tumor therapy. Front Oncol. 2014;4:254.CrossRef
30.
Rosati E, Sabatini R, Rampino G, Tabilio A, Di Ianni M, Fettucciari K, Bartoli A, Coaccioli S, Screpanti I, Marconi P. Constitutively activated Notch signaling is involved in survival and apoptosis resistance of B-CLL cells. Blood. 2009;113(4):856–65.CrossRef
31.
Jundt F, Anagnostopoulos I, Forster R, Mathas S, Stein H, Dorken B. Activated Notch1 signaling promotes tumor cell proliferation and survival in Hodgkin and anaplastic large cell lymphoma. Blood. 2002;99(9):3398–403.CrossRef
32.
Fiaschetti G, Schroeder C, Castelletti D, Arcaro A, Westermann F, Baumgartner M, Shalaby T, Grotzer MA. NOTCH ligands JAG1 and JAG2 as critical pro-survival factors in childhood medulloblastoma. Acta Neuropathol Commun. 2014;2:39.CrossRef
33.
Dai Y, Wilson G, Huang B, Peng M, Teng G, Zhang D, Zhang R, Ebert MP, Chen J, Wong BC, et al. Silencing of Jagged1 inhibits cell growth and invasion in colorectal cancer. Cell Death Dis. 2014;5:e1170.CrossRef
34.
Reedijk M, Odorcic S, Chang L, Zhang H, Miller N, McCready DR, Lockwood G, Egan SE. High-level coexpression of JAG1 and NOTCH1 is observed in human breast cancer and is associated with poor overall survival. Cancer Res. 2005;65(18):8530–7.CrossRef
35.
LaVoie MJ, Selkoe DJ. The Notch ligands, Jagged and Delta, are sequentially processed by alpha-secretase and presenilin/gamma-secretase and release signaling fragments. J Biol Chem. 2003;278(36):34427–37.CrossRef
36.
Zeng Q, Li S, Chepeha DB, Giordano TJ, Li J, Zhang H, Polverini PJ, Nor J, Kitajewski J, Wang CY. Crosstalk between tumor and endothelial cells promotes tumor angiogenesis by MAPK activation of Notch signaling. Cancer Cell. 2005;8(1):13–23.CrossRef
37.
Nickoloff BJ, Qin JZ, Chaturvedi V, Denning MF, Bonish B, Miele L. Jagged-1 mediated activation of notch signaling induces complete maturation of human keratinocytes through NF-kappaB and PPARgamma. Cell Death Differ. 2002;9(8):842–55.CrossRef
Metadata
Title
JAG1 overexpression contributes to Notch1 signaling and the migration of HTLV-1-transformed ATL cells
Authors
Marcia Bellon
Ramona Moles
Hassiba Chaib-Mezrag
Joanna Pancewicz
Christophe Nicot
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2018
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-018-0665-6

Other articles of this Issue 1/2018

Journal of Hematology & Oncology 1/2018 Go to the issue

Research

CAR-T cells targeting CLL-1 as an approach to treat acute myeloid leukemia

Research

STARD13-correlated ceRNA network-directed inhibition on YAP/TAZ activity suppresses stemness of breast cancer via co-regulating Hippo and Rho-GTPase/F-actin signaling

Research

Long non-coding RNA-SNHG7 acts as a target of miR-34a to increase GALNT7 level and regulate PI3K/Akt/mTOR pathway in colorectal cancer progression

Review

Role of platelets and platelet receptors in cancer metastasis

Review

Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) in cancer

Research

DACH1 antagonizes CXCL8 to repress tumorigenesis of lung adenocarcinoma and improve prognosis
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits