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High expression of <jats:italic>NTRK1<\/jats:italic>, encoding tropomyosin receptor kinase A (TrkA), confers a poor prognosis in other malignancies and may contribute to therapy resistance in patients with <jats:italic>ETV6::RUNX1<\/jats:italic> B\u2010ALL.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p>Relapse\u2010free survival was estimated by the Kaplan\u2013Meier and log\u2010rank analyses. <jats:italic>ETV6::RUNX1<\/jats:italic> and <jats:italic>NTRK1<\/jats:italic> were isolated from patient cDNA and transduced into IL\u20103\u2013dependent Ba\/F3 cells. Proliferation was assessed via CellTiter\u2010Glo\u20102.0 with the addition of the TrkA agonist, nerve growth factor (NGF). Sensitivity to the TRK inhibitor larotrectinib was assessed via Annexin V\/7AAD staining and flow cytometry. Changes in TrkA signalling through effectors, ERK and AKT, were evaluated by western blotting.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Patients with <jats:italic>ETV6::RUNX1<\/jats:italic> had increased <jats:italic>NTRK1<\/jats:italic> expression in comparison with other B\u2010ALL cases (<jats:italic>p<\/jats:italic> &lt; 0.0001), with those overexpressing <jats:italic>NTRK1<\/jats:italic> exhibiting a trend towards increased relapse. in vitro experiments revealed that only Ba\/F3 <jats:italic>ETV6::RUNX1<\/jats:italic>+<jats:italic>NTRK1<\/jats:italic> cells demonstrated IL\u20103 independence, indicative of leukaemic transformation (vs parental Ba\/F3, <jats:italic>p<\/jats:italic> &lt; 0.0001). These cells were sensitive to larotrectinib (LD<jats:sub>50<\/jats:sub> 161\u00a0nM) and significantly decreased phosphorylation of ERK and AKT (vs NGF <jats:italic>p =<\/jats:italic> 0.0004; <jats:italic>p =<\/jats:italic> 0.007, respectively).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p><jats:italic>NTRK1<\/jats:italic> overexpression has not previously been reported in B\u2010ALL and was associated with increased relapse in patients with <jats:italic>ETV6::RUNX1<\/jats:italic> and <jats:italic>NTKR1<\/jats:italic> overexpression. The in vitro success of larotrectinib treatment warrants further in vivo investigation and may be a viable therapeutic addition for patients with <jats:italic>ETV6::RUNX1<\/jats:italic> B\u2010ALL and <jats:italic>NTRK1<\/jats:italic> overexpression.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pbc.31983","type":"journal-article","created":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T07:14:49Z","timestamp":1756365289000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["High Expression of <i>NTRK1<\/i> in <i>ETV6::RUNX1<\/i> Positive Acute Lymphoblastic Leukaemia Drives Factor Independence and Sensitivity to Larotrectinib"],"prefix":"10.1002","volume":"72","author":[{"given":"Luke","family":"Quinlan","sequence":"first","affiliation":[{"name":"South Australian Health and Medical Research Institute (SAHMRI) Blood Cancer Program, Precision Cancer Medicine Theme  Adelaide South Australia Australia"},{"name":"Faculty of 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