T 细胞急性淋巴细胞白血病 (T-ALL) 和 T 细胞淋巴母细胞淋巴瘤 (T-LBL) 是罕见的侵袭性血液恶性肿瘤。目前的治疗方法包括强化化疗，总体生存率可达 80%，但会产生严重的毒副作用。此外，10-20% 的患者仍然死于复发或难治性疾病，这为制定更具体、更有针对性、毒性更小的治疗策略提供了强有力的理由。在这里，我们报告了 T-LBL 患者中的一种新型 MYH9::PDGFRB 融合，并证明该融合产物具有组成型活性，足以在体外和体内驱动致癌转化。将我们的分析扩展到 T-ALL 更广泛的范围，我们发现 T-ALL 细胞系和多个患者衍生的异种移植模型在没有融合的情况下具有 PDGFRB 过度激活，并且在 TLX3 和 HOXA T-ALL 分子亚型中具有高 PDGFRB 表达。为了针对这种 PDGFRB 过度激活，我们在体外和体内评估了选择性 PDGFRB 抑制剂 CP-673451 的治疗效果，并证明了受体过度激活时的敏感性。总而言之，我们的工作揭示了 PDGFRB 的过度激活是 T-ALL/T-LBL 的致癌驱动因素，并且筛查 T-ALL/TLBL 患者的磷酸化 PDGFRB 水平可以作为 PDGFRB 抑制的生物标志物，作为其新的靶向治疗策略。治疗方案。

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.