High Expression of NTRK1 in ETV6::RUNX1 Positive Acute Lymphoblastic Leukaemia Drives Factor Independence and Sensitivity to Larotrectinib.
Date
2025
Authors
Quinlan, L.
Page, E.C.
Rehn, J.
McClure, B.J.
Osborn, M.P.
Moore, A.S.
Kotecha, R.S.
Henderson, M.J.
Martin, M.
Alvaro, F.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
Pediatric Blood and Cancer, 2025; 72(11):e31983-1-e31983-7
Statement of Responsibility
Luke Quinlan, Elyse C. Page, Jacqueline Rehn, Barbara J. McClure, Michael P. Osborn, Andrew S. Moore, Rishi S. Kotecha, Michelle J. Henderson, Michelle Martin, Frank Alvaro, David T. Yeung, Deborah L. White, Susan L. Heatley
Conference Name
Abstract
Background: ETV6::RUNX1 is one of the most common recurrent genomic abnormalities in acute lymphoblastic leukaemia (ALL) and is associated with a good prognosis. High expression of NTRK1, encoding tropomyosin receptor kinase A (TrkA), confers a poor prognosis in other malignancies and may contribute to therapy resistance in patients with ETV6::RUNX1 B-ALL. Method: Relapse-free survivalwas estimated by the Kaplan–Meier and log-rank analyses. ETV6::RUNX1 and NTRK1 were isolated from patient cDNA and transduced into IL-3–dependent Ba/F3 cells. Proliferation was assessed via CellTiter-Glo-2.0 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. Results: Patients with ETV6::RUNX1 had increased NTRK1 expression in comparison with other B-ALL cases (p < 0.0001), with those overexpressing NTRK1 exhibiting a trend towards increased relapse. in vitro experiments revealed that only Ba/F3 ETV6::RUNX1+NTRK1 cells demonstrated IL-3 independence, indicative of leukaemic transformation (vs parental Ba/F3, p < 0.0001). These cells were sensitive to larotrectinib (LD50 161 nM) and significantly decreased phosphorylation of ERK and AKT (vs NGF p = 0.0004; p = 0.007, respectively).Conclusion: NTRK1 overexpression has not previously been reported in B-ALL and was associated with increased relapse in patients with ETV6::RUNX1 and NTKR1 overexpression. The in vitro success of larotrectinib treatment warrants further in vivo investigation and may be a viable therapeutic addition for patients with ETV6::RUNX1 B-ALL and NTRK1 overexpression.
School/Discipline
Dissertation Note
Provenance
Description
Access Status
Rights
© 2025 Wiley Periodicals LLC.