Targeting hyperactive platelet-derived growth factor receptor-β signaling in T-cell acute lymphoblastic leukemia and lymphoma

• Published in: Haematologica (Roma) Vol. 109; no. 5; pp. 1373 - 1384
• Main Authors: De Coninck, Stien, De Smedt, Renate, Lintermans, Beatrice, Reunes, Lindy, Kosasih, Hansen J., Reekmans, Alexandra, Brown, Lauren M., Van Roy, Nadine, Palhais, Bruno, Roels, Juliette, Van der Linden, Malaika, Van Dorpe, Jo, Ntziachristos, Panagiotis, Van Delft, Frederik W., Mansour, Marc R., Pieters, Tim, Lammens, Tim, De Moerloose, Barbara, De Bock, Charles E., Goossens, Steven, Van Vlierberghe, Pieter
• Format: Journal Article
• Language: English
• Published: Italy Fondazione Ferrata Storti 01.05.2024; Ferrata Storti Foundation
• Subjects: Acute Lymphoblastic Leukemia; Animals; Cell Line, Tumor; Disease Models, Animal; Humans; Mice; Molecular Targeted Therapy; Myosin Heavy Chains - genetics; Myosin Heavy Chains - metabolism; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Receptor, Platelet-Derived Growth Factor beta - antagonists & inhibitors; Receptor, Platelet-Derived Growth Factor beta - genetics; Receptor, Platelet-Derived Growth Factor beta - metabolism; Signal Transduction - drug effects; Xenograft Model Antitumor Assays
• ISSN: 0390-6078; 1592-8721; 1592-8721
• DOI: 10.3324/haematol.2023.283981

T cell acute lymphoblastic leukemia (T-ALL) and T cell lymphoblastic lymphoma (T-LBL) are rare aggressive hematological malignancies. Current treatment consists of intensive chemotherapy, leading to 80% overall survival but are 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/TLBL patients for phosphorylated PDGFRB levels can serve as a biomarker for PDGFRB inhibition as a novel targeted therapeutic strategy in their treatment regimen.