Haematologica (Nov 2023)

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

  • 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

DOI
https://doi.org/10.3324/haematol.2023.283981
Journal volume & issue
Vol. 109, no. 5

Abstract

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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.