Targeting hyperactive platelet-derived growth factor receptor-β signaling in T-cell acute lymphoblastic leukemia and lymphoma
| Title: | Targeting hyperactive platelet-derived growth factor receptor-β signaling in T-cell acute lymphoblastic leukemia and lymphoma |
|---|---|
| Authors: | Stien De Coninck, Renate De Smedt, Beatrice Lintermans, Lindy Reunes, Hansen J. Kosasih, Alexandra Reekmans, Lauren M. Brown, Nadine Van Roy, Bruno Palhais, Juliette Roels, Malaika 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, Pieter Van Vlierberghe |
| Source: | Haematologica, Vol 109, Iss 5 (2023) |
| Publisher Information: | Ferrata Storti Foundation, 2023. |
| Publication Year: | 2023 |
| Collection: | LCC:Diseases of the blood and blood-forming organs |
| Subject Terms: | Diseases of the blood and blood-forming organs, RC633-647.5 |
| More Details: | 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. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 0390-6078 1592-8721 |
| Relation: | https://haematologica.org/article/view/11338; https://doaj.org/toc/0390-6078; https://doaj.org/toc/1592-8721 |
| DOI: | 10.3324/haematol.2023.283981 |
| Access URL: | https://doaj.org/article/a08f66779ce943b3bf87b6b00741dfb3 |
| Accession Number: | edsdoj.08f66779ce943b3bf87b6b00741dfb3 |
| Database: | Directory of Open Access Journals |
| ISSN: | 03906078 15928721 |
|---|---|
| DOI: | 10.3324/haematol.2023.283981 |
| Published in: | Haematologica |
| Language: | English |