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Although T-ALL prognosis has improved markedly in recent years, relapsing and refractory patients with dismal outcomes still represent a major clinical issue. Consequently, understanding the pathological mechanisms that lead to the appearance of this malignancy and developing novel and more effective targeted therapies is an urgent need. Since the discovery in 2004 that a major proportion of T-ALL patients carry activating mutations that turn NOTCH1 into an oncogene, great efforts have been made to decipher the mechanisms underlying constitutive NOTCH1 activation, with the aim of understanding how NOTCH1 dysregulation converts the physiological NOTCH1-dependent T-cell developmental program into a pathological T-cell transformation process. Several molecular players have so far been shown to cooperate with NOTCH1 in this oncogenic process, and different therapeutic strategies have been developed to specifically target NOTCH1-dependent T-ALLs. Here, we comprehensively analyze the molecular bases of the cross-talk between NOTCH1 and cooperating partners critically involved in the generation and\/or maintenance and progression of T-ALL and discuss novel opportunities and therapeutic approaches that current knowledge may open for future treatment of T-ALL patients.<\/jats:p>","DOI":"10.3390\/ijms24021383","type":"journal-article","created":{"date-parts":[[2023,1,11]],"date-time":"2023-01-11T02:06:03Z","timestamp":1673402763000},"page":"1383","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Notch Partners in the Long Journey of T-ALL Pathogenesis"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8637-0373","authenticated-orcid":false,"given":"Mar\u00eda Luisa","family":"Toribio","sequence":"first","affiliation":[{"name":"Immune System Development and Function Unit, Centro de Biolog\u00eda Molecular Severo Ochoa, Consejo Superior de Investigaciones Cient\u00edficas (CSIC), Universidad Aut\u00f3noma de Madrid (UAM), 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Gonz\u00e1lez-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Immune System Development and Function Unit, Centro de Biolog\u00eda Molecular Severo Ochoa, Consejo Superior de Investigaciones Cient\u00edficas (CSIC), Universidad Aut\u00f3noma de Madrid (UAM), 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1126\/science.284.5415.770","article-title":"Notch Signaling: Cell Fate Control and Signal Integration in Development","volume":"284","author":"Rand","year":"1999","journal-title":"Science"},{"key":"ref_2","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_3","first-page":"47","article-title":"Notch1 and IL-7 Receptor Signalling in Early T-Cell Development and Leukaemia","volume":"360","author":"Alcain","year":"2012","journal-title":"Curr. 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