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

Stien De Coninck (UGent) , Renate De Smedt (UGent) , Béatrice Lintermans (UGent) , Lindy Reunes (UGent) , Hansen J. Kosasih, Alexandra Reekmans (UGent) , Lauren M. Brown, Nadine Van Roy (UGent) , Bruno Palhais (UGent) , Juliette Roels (UGent) , et al.
(2024) HAEMATOLOGICA. 109(5). p.1373-1384
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Abstract
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.
Keywords
Hematology

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MLA
De Coninck, Stien, et al. “Targeting Hyperactive Platelet-Derived Growth Factor Receptor-β Signaling in T-Cell Acute Lymphoblastic Leukemia and Lymphoma.” HAEMATOLOGICA, vol. 109, no. 5, 2024, pp. 1373–84, doi:10.3324/haematol.2023.283981.
APA
De Coninck, S., De Smedt, R., Lintermans, B., Reunes, L., Kosasih, H. J., Reekmans, A., … Van Vlierberghe, P. (2024). Targeting hyperactive platelet-derived growth factor receptor-β signaling in T-cell acute lymphoblastic leukemia and lymphoma. HAEMATOLOGICA, 109(5), 1373–1384. https://doi.org/10.3324/haematol.2023.283981
Chicago author-date
De Coninck, Stien, Renate De Smedt, Béatrice Lintermans, Lindy Reunes, Hansen J. Kosasih, Alexandra Reekmans, Lauren M. Brown, et al. 2024. “Targeting Hyperactive Platelet-Derived Growth Factor Receptor-β Signaling in T-Cell Acute Lymphoblastic Leukemia and Lymphoma.” HAEMATOLOGICA 109 (5): 1373–84. https://doi.org/10.3324/haematol.2023.283981.
Chicago author-date (all authors)
De Coninck, Stien, Renate De Smedt, Béatrice Lintermans, Lindy Reunes, Hansen J. Kosasih, Alexandra Reekmans, Lauren M. Brown, Nadine Van Roy, Bruno Palhais, Juliette Roels, Malaïka Van der Linden, Jo Van Dorpe, Panagiotis Ntziachristos, Frederik W. Van Delft, Marc R. Mansour, Tim Pieters, Tim Lammens, Barbara De Moerloose, Charles E. De Bock, Steven Goossens, and Pieter Van Vlierberghe. 2024. “Targeting Hyperactive Platelet-Derived Growth Factor Receptor-β Signaling in T-Cell Acute Lymphoblastic Leukemia and Lymphoma.” HAEMATOLOGICA 109 (5): 1373–1384. doi:10.3324/haematol.2023.283981.
Vancouver
1.
De Coninck S, De Smedt R, Lintermans B, Reunes L, Kosasih HJ, Reekmans A, et al. Targeting hyperactive platelet-derived growth factor receptor-β signaling in T-cell acute lymphoblastic leukemia and lymphoma. HAEMATOLOGICA. 2024;109(5):1373–84.
IEEE
[1]
S. De Coninck et al., “Targeting hyperactive platelet-derived growth factor receptor-β signaling in T-cell acute lymphoblastic leukemia and lymphoma,” HAEMATOLOGICA, vol. 109, no. 5, pp. 1373–1384, 2024.
@article{01HF6H92Q0G8ZFYQJ6M9NJ4V94,
  abstract     = {{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.}},
  author       = {{De Coninck, Stien and De Smedt, Renate and Lintermans, Béatrice and Reunes, Lindy and Kosasih, Hansen J. and Reekmans, Alexandra and Brown, Lauren M. and Van Roy, Nadine and Palhais, Bruno and Roels, Juliette and Van der Linden, Malaïka and Van Dorpe, Jo and Ntziachristos, Panagiotis and Van Delft, Frederik W. and Mansour, Marc R. and Pieters, Tim and Lammens, Tim and De Moerloose, Barbara and De Bock, Charles E. and Goossens, Steven and Van Vlierberghe, Pieter}},
  issn         = {{0390-6078}},
  journal      = {{HAEMATOLOGICA}},
  keywords     = {{Hematology}},
  language     = {{eng}},
  number       = {{5}},
  pages        = {{1373--1384}},
  title        = {{Targeting hyperactive platelet-derived growth factor receptor-β signaling in T-cell acute lymphoblastic leukemia and lymphoma}},
  url          = {{http://doi.org/10.3324/haematol.2023.283981}},
  volume       = {{109}},
  year         = {{2024}},
}
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