{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T17:28:12Z","timestamp":1788197292471,"version":"build-2803163510"},"reference-count":94,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T00:00:00Z","timestamp":1771804800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"vzw Kinderkankerfonds","award":["Grant to TL"],"award-info":[{"award-number":["Grant to TL"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>T-cell lymphoblastic lymphoma (T-LBL) is an aggressive malignancy of immature T-cells accounting for a substantial proportion of pediatric non-Hodgkin lymphoma cases. Current chemotherapeutic regimens achieve five-year event-free survival rates of 80\u201390%, yet relapse occurs in approximately 20% of patients and remains a major therapeutic challenge. This underscores the need for improved, molecularly informed treatment strategies. Recent genomic profiling has highlighted the central role of NOTCH1 signaling in T-LBL pathogenesis. NOTCH1, a transmembrane receptor critical for T-cell differentiation and maturation, requires tightly regulated activation during normal thymocyte development. Dysregulated signaling disrupts this balance, driving aberrant proliferation and impaired differentiation, characteristics of malignant transformation. While activating mutations have long been recognized as key oncogenic events, the recent identification of recurrent NOTCH1 translocations, associated with adverse outcomes, reveals an additional mechanism of pathway activation. These findings reinforce NOTCH1 as a pivotal oncogenic hub in T-cell malignancies and a compelling target for therapeutic intervention. This review synthesizes current insights into the molecular landscape of pediatric T-LBL, with a focus on the biological and clinical implications of NOTCH1 mutations and translocations. Furthermore, we examine emerging approaches to therapeutically exploit aberrant NOTCH1 signaling for the more precise and effective treatment of this disease and formulate outstanding research questions.<\/jats:p>","DOI":"10.3390\/ijms27042083","type":"journal-article","created":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T16:22:55Z","timestamp":1771863775000},"page":"2083","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Decoding NOTCH1: From T-Cell Development Guardian to Driver of Pediatric T-Cell Lymphoblastic Lymphoma"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-6384-315X","authenticated-orcid":false,"given":"Fran","family":"Leijnen","sequence":"first","affiliation":[{"name":"Department of Internal Medicine and Pediatrics, Ghent University, 9000 Ghent, Belgium"},{"name":"Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, 9000 Ghent, Belgium"},{"name":"Cancer Research Institute Ghent, 9000 Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8733-4027","authenticated-orcid":false,"given":"Tim","family":"Lammens","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Pediatrics, Ghent University, 9000 Ghent, Belgium"},{"name":"Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, 9000 Ghent, Belgium"},{"name":"Cancer Research Institute Ghent, 9000 Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"101449","DOI":"10.1016\/j.beha.2023.101449","article-title":"Diagnosis and management of lymphoblastic lymphoma in children, adolescents and young adults","volume":"36","author":"Temple","year":"2023","journal-title":"Best. Pract. Res. Clin. Haematol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1111\/bjh.15793","article-title":"Lymphoblastic lymphoma in children and adolescents: Review of current challenges and future opportunities","volume":"185","author":"Burkhardt","year":"2019","journal-title":"Br. J. Haematol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1007\/s00428-024-03980-9","article-title":"Pediatric lymphomas: Overview and diagnostic challenges","volume":"486","author":"Choi","year":"2025","journal-title":"Virchows Arch."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1111\/bjh.14017","article-title":"Current status and future directions of T-lymphoblastic lymphoma in children and adolescents","volume":"173","author":"Burkhardt","year":"2016","journal-title":"Br. J. Haematol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1111\/j.1365-2141.2005.05735.x","article-title":"The impact of age and gender on biology, clinical features and treatment outcome of non-Hodgkin lymphoma in childhood and adolescence","volume":"131","author":"Burkhardt","year":"2005","journal-title":"Br. J. Haematol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1111\/bjh.70053","article-title":"T-cell lymphoblastic lymphoma in children, adolescents and young adults","volume":"207","author":"Newman","year":"2025","journal-title":"Br. J. Haematol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Lenz, G., and Salles, G. (2019). Pathology and Molecular Pathogenesis of Burkitt Lymphoma and Lymphoblastic Lymphoma. Aggressive Lymphomas, Springer.","DOI":"10.1007\/978-3-030-00362-3"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2112","DOI":"10.1200\/JCO.2014.59.7203","article-title":"Revised International Pediatric Non-Hodgkin Lymphoma Staging System","volume":"33","author":"Rosolen","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_9","first-page":"332","article-title":"Classification, staging and end results of treatment of childhood non-Hodgkin\u2019s lymphomas: Dissimilarities from lymphomas in adults","volume":"7","author":"Murphy","year":"1980","journal-title":"Semin. Oncol."},{"key":"ref_10","unstructured":"Attarbaschi, A., Beishuizen, A., Mann, G., Rosolen, A., and Burkhardt, B. (2021). European Standard Clinical Practice Recommendations for Non-Hodgkin Lymphoma of Childhood and Adolescence, European Intergroup for Childhood Non-Hodgkin Lymphoma (EICNHL)."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3466","DOI":"10.1182\/bloodadvances.2020001822","article-title":"T-cell lymphoblastic lymphoma and leukemia: Different diseases from a common premalignant progenitor?","volume":"4","author":"Kroeze","year":"2020","journal-title":"Blood Adv."},{"key":"ref_12","unstructured":"WHO Classification of Tumours Editorial Board (2024). WHO Classification of Tumours: Haematolymphoid Tumours, International Agency for Research on Cancer (IARC), World Health Organization. [5th ed.]."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1182\/blood.V84.5.1361.1361","article-title":"A Revised European-American Classification of Lymphoid Neoplasms: A Proposal from the International Lymphoma Study Group","volume":"84","author":"Harris","year":"1994","journal-title":"Blood"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1002\/pbc.20550","article-title":"Gene expression profiling reveals intrinsic differences between T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma","volume":"47","author":"Raetz","year":"2006","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e117","DOI":"10.1002\/hem3.117","article-title":"NOTCH1 fusions in pediatric T-cell lymphoblastic lymphoma: A high-risk subgroup with CCL17 (TARC) levels as diagnostic biomarker","volume":"8","author":"Kroeze","year":"2024","journal-title":"Hemasphere"},{"key":"ref_16","first-page":"416","article-title":"Intensive ALL-type therapy without local radiotherapy provides a 90% event-free survival for children with T-cell lymphoblastic lymphoma: A BFM Group report","volume":"95","author":"Reiter","year":"2000","journal-title":"Blood"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2086","DOI":"10.3324\/haematol.2015.139162","article-title":"Results and conclusions of the European Intergroup EURO-LB02 trial in children and adolescents with lymphoblastic lymphoma","volume":"102","author":"Landmann","year":"2017","journal-title":"Haematologica"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3363","DOI":"10.1200\/JCO.2008.19.3367","article-title":"Poor Outcome for Children and Adolescents with Progressive Disease or Relapse of Lymphoblastic Lymphoma: A Report from the Berlin-Frankfurt-Muenster Group","volume":"27","author":"Burkhardt","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_19","first-page":"3019","article-title":"How I treat newly diagnosed and refractory T-cell acute lymphoblastic lymphoma in children and young adults","volume":"141","author":"Ford","year":"2023","journal-title":"Blood"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1182\/blood.2024025307","article-title":"Pediatric T-cell lymphoblastic lymphomas but not leukemias harbor TRB::NOTCH1 fusions with unfavorable outcome","volume":"144","author":"Wessolowski","year":"2024","journal-title":"Blood"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1038\/s41379-022-01085-9","article-title":"Oncogenetic landscape of T-cell lymphoblastic lymphomas compared to T-cell acute lymphoblastic leukemia","volume":"35","author":"Bontoux","year":"2022","journal-title":"Mod. Pathol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2347","DOI":"10.1182\/blood.2020005381","article-title":"Integrative genomic analysis of pediatric T-cell lymphoblastic lymphoma reveals candidates of clinical significance","volume":"137","author":"Khanam","year":"2021","journal-title":"Blood"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3153","DOI":"10.1182\/blood-2012-12-474148","article-title":"Incidence and prognostic relevance of genetic variations in T-cell lymphoblastic lymphoma in childhood and adolescence","volume":"121","author":"Bonn","year":"2013","journal-title":"Blood"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1038\/leu.2015.203","article-title":"Proposal of a genetic classifier for risk group stratification in pediatric T-cell lymphoblastic lymphoma reveals differences from adult T-cell lymphoblastic leukemia","volume":"30","author":"Balbach","year":"2016","journal-title":"Leukemia"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Veltri, G., Silvestri, C., Gallingani, I., Sandei, M., Vencato, S., Lovisa, F., Cortese, G., Pillon, M., Carraro, E., and Bresolin, S. (2021). Ruxolitinib as a Novel Therapeutic Option for Poor Prognosis T-LBL Pediatric Patients. Cancers, 13.","DOI":"10.3390\/cancers13153724"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"100029","DOI":"10.1016\/j.bneo.2024.100029","article-title":"T-cell lymphoblastic lymphoma compared with T-cell acute lymphoblastic leukemia: Similar subtypes and different fusions","volume":"1","author":"Kroeze","year":"2024","journal-title":"Blood Neoplasia"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2369","DOI":"10.1182\/blood.V99.7.2369","article-title":"Notch1 activation increases hematopoietic stem cell self-renewal in vivo and favors lymphoid over myeloid lineage outcome","volume":"99","author":"Stier","year":"2002","journal-title":"Blood"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"921706","DOI":"10.5402\/2011\/921706","article-title":"Notch Signaling in T-Cell Development and T-ALL","volume":"2011","author":"Li","year":"2011","journal-title":"ISRN Hematol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.cell.2009.03.045","article-title":"The Canonical Notch Signaling Pathway: Unfolding the Activation Mechanism","volume":"137","author":"Kopan","year":"2009","journal-title":"Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1182\/asheducation-2009.1.353","article-title":"The role of NOTCH1 signaling in T-ALL","volume":"2009","author":"Ferrando","year":"2009","journal-title":"Hematology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/s12079-015-0271-0","article-title":"The NOTCH signaling pathway in normal and malignant blood cell production","volume":"9","author":"Suresh","year":"2015","journal-title":"J. Cell Commun. Signal."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1359\/jbmr.060505","article-title":"Role of the Ram Domain and Ankyrin Repeats on Notch Signaling and Activity in Cells of Osteoblastic Lineage","volume":"21","author":"Deregowski","year":"2009","journal-title":"J. Bone Miner. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/S0952-7915(99)00067-9","article-title":"Notch signaling in T cell development","volume":"12","author":"Deftos","year":"2000","journal-title":"Curr. Opin. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1084\/jem.194.7.1003","article-title":"Notch 1\u2013Deficient Common Lymphoid Precursors Adopt a B Cell Fate in the Thymus","volume":"194","author":"Wilson","year":"2001","journal-title":"J. Exp. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/S1074-7613(00)80054-0","article-title":"Deficient T cell fate specification in mice with an induced inactivation of Notch1","volume":"10","author":"Radtke","year":"1999","journal-title":"Immunity"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1146\/annurev.immunol.23.021704.115737","article-title":"Molecular genetics of T cell development","volume":"23","author":"Rothenberg","year":"2005","journal-title":"Annu. Rev. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1084\/jem.20040394","article-title":"Maintenance of T cell specification and differentiation requires recurrent notch receptor-ligand interactions","volume":"200","author":"Schmitt","year":"2004","journal-title":"J. Exp. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1016\/S0092-8674(00)81929-7","article-title":"Notch Activity Influences the \u03b1\u03b2 versus \u03b3\u03b4 T Cell Lineage Decision","volume":"88","author":"Washburn","year":"1997","journal-title":"Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1016\/S1074-7613(02)00330-8","article-title":"Inactivation of Notch1 impairs VDJbeta rearrangement and allows pre-TCR-independent survival of early alpha beta Lineage Thymocytes","volume":"16","author":"Wolfer","year":"2002","journal-title":"Immunity"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2511","DOI":"10.1182\/blood-2011-04-346726","article-title":"Nonoverlapping functions for Notch1 and Notch3 during murine steady-state thymic lymphopoiesis","volume":"118","author":"Shi","year":"2011","journal-title":"Blood"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/S1044-5323(03)00007-1","article-title":"Notch3, another Notch in T cell development","volume":"15","author":"Bellavia","year":"2003","journal-title":"Semin. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5997","DOI":"10.4049\/jimmunol.1400764","article-title":"Notch3 activation is sufficient but not required for inducing human T-lineage specification","volume":"193","author":"Waegemans","year":"2014","journal-title":"J. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"6077","DOI":"10.1038\/onc.2016.133","article-title":"Characterization of activating mutations of NOTCH3 in T-cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies","volume":"35","author":"Hu","year":"2016","journal-title":"Oncogene"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e70613","DOI":"10.1096\/fj.202402997R","article-title":"Induction of T-Cell Differentiation by KLF4 in T-Cell Acute Lymphoblastic Leukemia Cells Harboring Activating Mutation in NOTCH3","volume":"39","author":"Noura","year":"2025","journal-title":"FASEB J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"4642","DOI":"10.1128\/MCB.01655-05","article-title":"Leukemia-associated mutations within the NOTCH1 heterodimerization domain fall into at least two distinct mechanistic classes","volume":"26","author":"Malecki","year":"2006","journal-title":"Mol. Cell Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1111\/ejh.12019","article-title":"A novel TRB@\/NOTCH1 fusion gene in T-cell lymphoblastic lymphoma with t(7;9)(q34;q34)","volume":"90","author":"Yamamoto","year":"2013","journal-title":"Eur. J. Haematol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1966","DOI":"10.1200\/JCO.2011.39.7661","article-title":"Clinical impact of NOTCH1 and\/or FBXW7 mutations, FLASH deletion, and TCR status in pediatric T-cell lymphoblastic lymphoma","volume":"30","author":"Callens","year":"2012","journal-title":"J. Clin. Oncol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"4618","DOI":"10.1182\/bloodadvances.2025015837","article-title":"Serum TARC: A biomarker for early detection or exclusion of relapse in classic Hodgkin lymphoma","volume":"9","author":"Teesink","year":"2025","journal-title":"Blood Adv."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"5516","DOI":"10.1158\/0008-5472.CAN-05-0100","article-title":"Elevated serum levels of CC thymus and activation-related chemokine (TARC) in primary Hodgkin\u2019s disease: Potential for a prognostic factor","volume":"65","author":"Weihrauch","year":"2005","journal-title":"Cancer Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"965","DOI":"10.4161\/cc.7.8.5753","article-title":"The role of the PTEN\/AKT Pathway in NOTCH1-induced leukemia","volume":"7","author":"Palomero","year":"2008","journal-title":"Cell Cycle"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1182\/blood-2011-12-395319","article-title":"HES1 opposes a PTEN-dependent check on survival, differentiation, and proliferation of TCR\u03b2-selected mouse thymocytes","volume":"120","author":"Wong","year":"2012","journal-title":"Blood"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1038\/nm1636","article-title":"Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia","volume":"13","author":"Palomero","year":"2007","journal-title":"Nat. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1182\/blood-2006-08-039883","article-title":"Notch signals positively regulate activity of the mTOR pathway in T-cell acute lymphoblastic leukemia","volume":"110","author":"Chan","year":"2007","journal-title":"Blood"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.cellsig.2013.09.021","article-title":"New insights into Notch1 regulation of the PI3K\u2013AKT\u2013mTOR1 signaling axis: Targeted therapy of \u03b3-secretase inhibitor resistant T-cell acute lymphoblastic leukemia","volume":"26","author":"Hales","year":"2014","journal-title":"Cell. Signal."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1084\/jem.20110121","article-title":"High-level IGF1R expression is required for leukemia-initiating cell activity in T-ALL and is supported by Notch signaling","volume":"208","author":"Medyouf","year":"2011","journal-title":"J. Exp. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1084\/jem.20081922","article-title":"CSL\u2013MAML-dependent Notch1 signaling controls T lineage\u2013specific IL-7R\u03b1 gene expression in early human thymopoiesis and leukemia","volume":"206","author":"Ballestar","year":"2009","journal-title":"J. Exp. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1084\/jem.20040789","article-title":"Activation of PI3K Is Indispensable for Interleukin 7\u2013mediated Viability, Proliferation, Glucose Use, and Growth of T Cell Acute Lymphoblastic Leukemia Cells","volume":"200","author":"Barata","year":"2004","journal-title":"J. Exp. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"3041","DOI":"10.1002\/eji.1830251109","article-title":"Interleukin-7 can induce the activation of Jak 1, Jak 3 and STAT 5 proteins in murine T cells","volume":"25","author":"Foxwell","year":"1995","journal-title":"Eur. J. Immunol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1124\/molpharm.120.000006","article-title":"Notch1 in Cancer Therapy: Possible Clinical Implications and Challenges","volume":"98","author":"Gharaibeh","year":"2020","journal-title":"Mol. Pharmacol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2096","DOI":"10.1101\/gad.1450406","article-title":"c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia\/lymphoma","volume":"20","author":"Weng","year":"2006","journal-title":"Genes. Dev."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"18261","DOI":"10.1073\/pnas.0606108103","article-title":"NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth","volume":"103","author":"Palomero","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2077","DOI":"10.1128\/MCB.18.4.2077","article-title":"NF-\u03baB2 Is a Putative Target Gene of Activated Notch-1 via RBP-J\u03ba","volume":"18","author":"Oswald","year":"1998","journal-title":"Mol. Cell. Biol."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Miele, L., and Artavanis-Tsakonas, S. (2018). Notch Signaling in T-Cell Acute Lymphoblastic Leukemia and Other Hematologic Malignancies. Targeting Notch in Cancer: From the Fruit Fly to the Clinic, Springer.","DOI":"10.1007\/978-1-4939-8859-4"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.ccr.2010.08.006","article-title":"The Notch\/Hes1 Pathway Sustains NF-\u03baB Activation through CYLD Repression in T Cell Leukemia","volume":"18","author":"Espinosa","year":"2010","journal-title":"Cancer Cell"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1038\/sj.emboj.7600902","article-title":"Notch1 augments NF-\u03baB activity by facilitating its nuclear retention","volume":"25","author":"Shin","year":"2006","journal-title":"EMBO J."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"4262","DOI":"10.1128\/MCB.25.10.4262-4271.2005","article-title":"Hes1 directly controls cell proliferation through the transcriptional repression of p27Kip1","volume":"25","author":"Murata","year":"2005","journal-title":"Mol. Cell Biol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3141","DOI":"10.1016\/j.yexcr.2007.04.027","article-title":"Notch signaling induces SKP2 expression and promotes reduction of p27Kip1 in T-cell acute lymphoblastic leukemia cell lines","volume":"313","author":"Dohda","year":"2007","journal-title":"Exp. Cell Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1689","DOI":"10.1182\/blood-2008-03-147967","article-title":"Notch signaling mediates G1\/S cell-cycle progression in T cells via cyclin D3 and its dependent kinases","volume":"113","author":"Joshi","year":"2009","journal-title":"Blood"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"3373","DOI":"10.1182\/blood-2008-03-147587","article-title":"K-RasG12D\u2013induced T-cell lymphoblastic lymphoma\/leukemias harbor Notch1 mutations and are sensitive to \u03b3-secretase inhibitors","volume":"112","author":"Kindler","year":"2008","journal-title":"Blood"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1038\/sj.leu.2404258","article-title":"CUTLL1, a novel human T-cell lymphoma cell line with t(7;9) rearrangement, aberrant NOTCH1 activation and high sensitivity to \u03b3-secretase inhibitors","volume":"20","author":"Palomero","year":"2006","journal-title":"Leukemia"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.chembiol.2006.12.010","article-title":"Apoptosis in T Cell Acute Lymphoblastic Leukemia Cells after Cell Cycle Arrest Induced by Pharmacological Inhibition of Notch Signaling","volume":"14","author":"Lewis","year":"2007","journal-title":"Chem. Biol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1111\/j.1476-5381.2009.00389.x","article-title":"Down-regulation of the Notch pathway mediated by a \u03b3-secretase inhibitor induces anti-tumour effects in mouse models of T-cell leukaemia","volume":"158","author":"Tammam","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"ref_73","first-page":"2507","article-title":"Combination therapy of a PSEN1-selective \u03b3-secretase inhibitor with dexamethasone and an XPO1 inhibitor to target T-cell acute lymphoblastic leukemia","volume":"108","author":"Vandersmissen","year":"2023","journal-title":"Haematologica"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/nm.1900","article-title":"\u03b3-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia","volume":"15","author":"Real","year":"2009","journal-title":"Nat. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"6172","DOI":"10.1182\/blood-2008-02-136762","article-title":"Targeting the Notch1 and mTOR pathways in a mouse T-ALL model","volume":"113","author":"Cullion","year":"2009","journal-title":"Blood"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1002\/cncr.33188","article-title":"Phase 1 study to evaluate Crenigacestat (LY3039478) in combination with dexamethasone in patients with T-cell acute lymphoblastic leukemia and lymphoma","volume":"127","author":"Borthakur","year":"2021","journal-title":"Cancer"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1182\/blood.V124.21.968.968","article-title":"The Safety and Activity of BMS-906024, a Gamma Secretase Inhibitor (GSI) with Anti-Notch Activity, in Patients with Relapsed T-Cell Acute Lymphoblastic Leukemia (T-ALL): Initial Results of a Phase 1 Trial","volume":"124","author":"DeAngelo","year":"2014","journal-title":"Blood"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"eaau6246","DOI":"10.1126\/scitranslmed.aau6246","article-title":"Safe targeting of T cell acute lymphoblastic leukemia by pathology-specific NOTCH inhibition","volume":"11","author":"Habets","year":"2019","journal-title":"Sci. Transl. Med."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1038\/leu.2013.183","article-title":"Therapeutic antibody targeting of Notch1 in T-acute lymphoblastic leukemia xenografts","volume":"28","author":"Agnusdei","year":"2014","journal-title":"Leukemia"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"5108","DOI":"10.1182\/blood.V128.22.5108.5108","article-title":"Safety and Preliminary Efficacy Results of a Phase I First-in-Human Study of the Novel Notch-1 Targeting Antibody Brontictuzumab (OMP-52M51) Administered Intravenously to Patients with Hematologic Malignancies","volume":"128","author":"Casulo","year":"2016","journal-title":"Blood"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1093\/carcin\/bgu223","article-title":"DLL4 regulates NOTCH signaling and growth of T acute lymphoblastic leukemia cells in NOD\/SCID mice","volume":"36","author":"Minuzzo","year":"2014","journal-title":"Carcinogenesis"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2695","DOI":"10.1158\/1078-0432.CCR-14-2797","article-title":"A Phase I First-in-Human Study of Enoticumab (REGN421), a Fully Human Delta-like Ligand 4 (Dll4) Monoclonal Antibody in Patients with Advanced Solid Tumors","volume":"21","author":"Chiorean","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"6295","DOI":"10.1158\/1078-0432.CCR-14-1373","article-title":"A Phase I Dose Escalation and Expansion Study of the Anticancer Stem Cell Agent Demcizumab (Anti-DLL4) in Patients with Previously Treated Solid Tumors","volume":"20","author":"Smith","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1016\/j.ccr.2013.01.015","article-title":"Complementary Genomic Screens Identify SERCA as a Therapeutic Target in NOTCH1 Mutated Cancer","volume":"23","author":"Roti","year":"2013","journal-title":"Cancer Cell"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1016\/j.chembiol.2020.04.002","article-title":"Blockade of Oncogenic NOTCH1 with the SERCA Inhibitor CAD204520 in T Cell Acute Lymphoblastic Leukemia","volume":"27","author":"Marchesini","year":"2020","journal-title":"Cell Chem. Biol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1038\/leu.2013.366","article-title":"Proteasome inhibitors exert cytotoxicity and increase chemosensitivity via transcriptional repression of Notch1 in T-cell acute lymphoblastic leukemia","volume":"28","author":"Koyama","year":"2014","journal-title":"Leukemia"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1007\/s00280-012-1953-4","article-title":"Bortezomib suppresses the growth of leukemia cells with Notch1 overexpression in vivo and in vitro","volume":"70","author":"Huang","year":"2012","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1111\/bjh.15919","article-title":"Bortezomib reinduction chemotherapy in high-risk ALL in first relapse: A report from the Children\u2019s Oncology Group","volume":"186","author":"Horton","year":"2019","journal-title":"Br. J. Haematol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2106","DOI":"10.1200\/JCO.21.02678","article-title":"Children\u2019s Oncology Group Trial AALL1231: A Phase III Clinical Trial Testing Bortezomib in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia and Lymphoma","volume":"40","author":"Teachey","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1038\/nature08543","article-title":"Direct inhibition of the NOTCH transcription factor complex","volume":"462","author":"Moellering","year":"2009","journal-title":"Nature"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"3593","DOI":"10.1158\/0008-5472.CAN-16-0061","article-title":"The Small Molecule IMR-1 Inhibits the Notch Transcriptional Activation Complex to Suppress Tumorigenesis","volume":"76","author":"Astudillo","year":"2016","journal-title":"Cancer Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"16292","DOI":"10.1073\/pnas.1922606117","article-title":"Pharmacological disruption of the Notch transcription factor complex","volume":"117","author":"Lehal","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1002\/jha2.510","article-title":"CB-103: A novel CSL-NICD inhibitor for the treatment of NOTCH-driven T-cell acute lymphoblastic leukemia: A case report of complete clinical response in a patient with relapsed and refractory T-ALL","volume":"3","author":"Medinger","year":"2022","journal-title":"EJHaem"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"10811","DOI":"10.1038\/s41598-019-46948-5","article-title":"Disruption of NOTCH signaling by a small molecule inhibitor of the transcription factor RBPJ","volume":"9","author":"Hurtado","year":"2019","journal-title":"Sci. Rep."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/4\/2083\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T16:23:40Z","timestamp":1771863820000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/4\/2083"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,23]]},"references-count":94,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["ijms27042083"],"URL":"https:\/\/doi.org\/10.3390\/ijms27042083","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,23]]}}}