{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T02:20:06Z","timestamp":1787019606257,"version":"build-2736575974"},"reference-count":34,"publisher":"American Society of Hematology","issue":"24","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,6,12]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>Refractory and\/or relapsing T-cell acute lymphoblastic leukemia (T-ALL) remains a major therapeutic challenge. The pre\u2013T-cell receptor (TCR) pathway has recently emerged as a therapeutic target via LCK inhibition in this context. However, there is a need for simple and quickly assessable biomarkers to predict sensitivity to LCK inhibitors. Moreover, targeting LCK alone by tyrosine kinase inhibitors, such as dasatinib, often results in transient clinical responses, emphasizing the need for efficient combination strategies. Here, we assessed pre-TCR \u03b1 chain (pT\u03b1) surface expression by flow cytometry in a unique series of 50 adult T-ALL patient-derived xenografts (PDXs). We show that cases displaying a cortical phenotype often express high levels of surface pT\u03b1 (pre-TCR+ T-ALL) and that the latter associates with LCK activation. Furthermore, we show that ectopic interleukin-7 receptor (IL-7R) expression can rescue pre-TCR+ T-ALL from dasatinib cytotoxicity (5 PDXs). We tested whether coinhibition of pre-TCR and IL-7R signaling pathways could be synergetic in pre-TCR+ IL-7R+ T-ALL (11 PDXs). Combination of JAK inhibitors, ruxolitinib or tofacitinib, with dasatinib elicited strong and specific synergy in IL-7R+ pre-TCR+ T-ALL in vitro, including in the relapse setting (4 of 28 patient-derived primary samples). Using 3 adult-PDX models, we show that in vivo treatment with this combination significantly delayed leukemic progression and prolonged survival compared with either monotherapy. This preclinical study thus proposes the use of pT\u03b1 as a biomarker of LCK-inhibitor sensitivity in T-ALL, and suggests that dual targeting of IL-7R and pre-TCR signaling pathways may be a relevant therapeutic strategy in a substantial proportion of adult T-ALL.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2024027982","type":"journal-article","created":{"date-parts":[[2025,2,20]],"date-time":"2025-02-20T15:59:27Z","timestamp":1740067167000},"page":"2903-2913","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":6,"title":["Surface pT\u03b1 expression predicts LCK activation and preclinical synergy of LCK and JAK coinhibition in adult T-ALL"],"prefix":"10.1182","volume":"145","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4156-3008","authenticated-orcid":false,"given":"Lucien","family":"Courtois","sequence":"first","affiliation":[{"name":"1INSERM Unit\u00e9 Mixte de Recherche (UMR)-S1151, Centre National de la Recherche Scientifique UMR-S8253, Institut Necker Enfants Malades, Universit\u00e9 Paris Cit\u00e9, Paris, France"},{"name":"2H\u00f4pital Necker Enfants-Malades, Laboratory of Onco-Hematology, Assistance Publique\u2013H\u00f4pitaux de Paris, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2801-6824","authenticated-orcid":false,"given":"Antoine","family":"Pinton","sequence":"additional","affiliation":[{"name":"1INSERM Unit\u00e9 Mixte de Recherche (UMR)-S1151, Centre National de la Recherche Scientifique UMR-S8253, Institut Necker Enfants Malades, Universit\u00e9 Paris Cit\u00e9, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6064-3783","authenticated-orcid":false,"given":"Aur\u00e9lie","family":"Cabannes-Hamy","sequence":"additional","affiliation":[{"name":"3Department of Hematology, Centre Hospitalier de Versailles, Universit\u00e9 Paris-Saclay, UMR1184, Le Chesnay Rocquencourt, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0448-8811","authenticated-orcid":false,"given":"Mathieu","family":"Simonin","sequence":"additional","affiliation":[{"name":"1INSERM Unit\u00e9 Mixte de Recherche (UMR)-S1151, Centre National de la Recherche Scientifique UMR-S8253, Institut Necker Enfants Malades, Universit\u00e9 Paris Cit\u00e9, Paris, France"},{"name":"4Department of Pediatric Hematology and Oncology, Armand Trousseau Hospital, Assistance Publique\u2013H\u00f4pitaux de Paris, Sorbonne Universit\u00e9, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0289-4952","authenticated-orcid":false,"given":"Guillaume P.","family":"Andrieu","sequence":"additional","affiliation":[{"name":"1INSERM Unit\u00e9 Mixte de Recherche (UMR)-S1151, Centre National de la Recherche Scientifique UMR-S8253, Institut Necker Enfants Malades, Universit\u00e9 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France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herv\u00e9","family":"Dombret","sequence":"additional","affiliation":[{"name":"6Institut de Recherche Saint-Louis, EA-3518, Universit\u00e9 Paris Cit\u00e9, Paris, France"},{"name":"7Department of Hematology, Saint Louis University Hospital, Assistance Publique\u2013H\u00f4pitaux de Paris, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7445-1005","authenticated-orcid":false,"given":"Andr\u00e9","family":"Baruchel","sequence":"additional","affiliation":[{"name":"5Department of Pediatric Hematology, Robert Debr\u00e9 Hospital, Assistance Publique\u2013H\u00f4pitaux de Paris, Universit\u00e9 Paris Cit\u00e9, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2091-7927","authenticated-orcid":false,"given":"Nicolas","family":"Boissel","sequence":"additional","affiliation":[{"name":"6Institut de 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