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Lookup NU author(s): Dr Frederik van DelftORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).
T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) are rare aggressive hematologic malignancies. Current treatment consists of intensive chemotherapy leading to 80% overall survival but is associated with severe toxic side effects. Furthermore, 10-20% of patients still die from relapsed or refractory disease providing a strong rationale for more specific, targeted therapeutic strategies with less toxicities. Here, we report a novel MYH9::PDGFRB fusion in a T-LBL patient, and demonstrate that this fusion product is constitutively active and sufficient to drive oncogenic transformation in vitro and in vivo. Expanding our analysis more broadly across T-ALL, we found a T-ALL cell line and multiple patient-derived xenograft models with PDGFRB hyperactivation in the absence of a fusion, with high PDGFRB expression in TLX3 and HOXA T-ALL molecular subtypes. To target this PDGFRB hyperactivation, we evaluated the therapeutic effects of a selective PDGFRB inhibitor, CP-673451, both in vitro and in vivo and demonstrated sensitivity if the receptor is hyperactivated. Altogether, our work reveals that hyperactivation of PDGFRB is an oncogenic driver in T-ALL/T-LBL, and that screening T-ALL/T-LBL patients for phosphorylated PDGFRB levels can serve as a biomarker for PDGFRB inhibition as a novel targeted therapeutic strategy in their treatment regimen.
Author(s): De Coninck S, De Smedt R, Lintermans B, Reunes L, Kosasih HJ, Reekmans A, Brown LM, Van Roy N, Palhais B, Roels J, Van der Linden M, Van Dorpe J, Ntziachristos P, Van Delft FW, Mansour MR, Pieters T, Lammens T, De Moerloose B, De Bock CE, Goossens S, Van Vlierberghe P
Publication type: Article
Publication status: Published
Journal: Haematologica
Year: 2024
Volume: 109
Issue: 5
Pages: 1373-1384
Print publication date: 01/05/2024
Acceptance date: 02/11/2023
Date deposited: 14/05/2024
ISSN (print): 0390-6078
ISSN (electronic): 1592-8721
Publisher: Elsevier
URL: https://doi.org/10.3324/haematol.2023.283981
DOI: 10.3324/haematol.2023.283981
PubMed id: 37941480
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