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

Autor:	De Coninck S; Lab of Normal and Malignant Hematopoiesis, Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), 9000 Ghent., De Smedt R; Lab of Normal and Malignant Hematopoiesis, Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), 9000 Ghent., Lintermans B; Lab of Normal and Malignant Hematopoiesis, Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), 9000 Ghent., Reunes L; Lab of Normal and Malignant Hematopoiesis, Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium; Department of Biomolecular Medicine, Ghent University, 9000 Ghent., Kosasih HJ; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia; School of Clinical Medicine, UNSW Medicine and Health, UNSW Sydney, Sydney, NSW., Reekmans A; Lab of Normal and Malignant Hematopoiesis, Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), 9000 Ghent., Brown LM; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia; School of Clinical Medicine, UNSW Medicine and Health, UNSW Sydney, Sydney, NSW., Van Roy N; Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium; Lab for Translational Oncogenomics and Bioinformatics, Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium; Pediatric Precision Oncology Lab, Department of Biomolecular Medicine, Ghent University, 9000 Ghent., Palhais B; Lab of Normal and Malignant Hematopoiesis, Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium; Department of Biomolecular Medicine, Ghent University, 9000 Ghent., Roels J; Lab of Normal and Malignant Hematopoiesis, Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), 9000 Ghent., Van der Linden M; Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium; Department of Pathology, Ghent University and Ghent University Hospital, 9000 Ghent., Van Dorpe J; Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium; Department of Pathology, Ghent University and Ghent University Hospital, 9000 Ghent., Ntziachristos P; Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium; Department of Biomolecular Medicine, Ghent University, 9000 Ghent., Van Delft FW; Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle upon Tyne., Mansour MR; Department of Developmental Biology and Cancer, Institute of Child Health, University College London., Pieters T; Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium; Department of Biomolecular Medicine, Ghent University, 9000 Ghent., Lammens T; Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium; Department of Internal Medicine and Pediatrics, Ghent University, 9000 Ghent, Belgium; Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, 9000 Ghent., De Moerloose B; Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium; Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, 9000 Ghent., De Bock CE; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia; School of Clinical Medicine, UNSW Medicine and Health, UNSW Sydney, Sydney, NSW., Goossens S; Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium; Unit for Translational Research in Oncology, Department of Diagnostic Sciences, Ghent University, 9000 Ghent. steven.goossens@ugent.be., Van Vlierberghe P; Lab of Normal and Malignant Hematopoiesis, Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), 9000 Ghent.
Jazyk:	angličtina
Zdroj:	Haematologica [Haematologica] 2024 May 01; Vol. 109 (5), pp. 1373-1384. Date of Electronic Publication: 2024 May 01.
DOI:	10.3324/haematol.2023.283981
Abstrakt:	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.
Databáze:	MEDLINE
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