尽管 BCR::ABL1 酪氨酸激酶抑制剂 (TKI) 的开发使慢性粒细胞白血病 (CML) 成为可控制的疾病，但在急变期 (BP) 进展期间获得耐药性仍然是一个严峻的挑战。在这里，我们将 FLT3（急性髓系白血病 (AML) 最常见的突变驱动因素之一）重新定位为 BP-CML 的预后标志物和治疗靶点。我们生成了表达 BCR::ABL1 TKI 耐药 CML 细胞的 FLT3，并入组了阶段 -特定的 CML 患者队列，以获得未配对和配对的连续标本，并验证 FLT3 信号在 BP-CML 患者中的作用。我们在动物和患者研究中进行了多组学方法，通过建立 (1) FLT3 驱动的耐药性的分子机制，(2) FLT3 蛋白表达的诊断方法，证明 FLT3 作为 BP-CML 可行靶点的临床可行性和定位，（3）FLT3信号传导与CML预后之间的关联，以及（4）针对FLT3 CML患者的治疗策略。我们重新定位FLT3在BP-CML耐药性获得中的重要性，从而对FLT3 BP进行新分类-CML亚组。从机制上讲，CML 细胞中的 FLT3 表达激活了 FLT3-JAK-STAT3-TAZ-TEAD-CD36 信号通路，从而赋予对多种 BCR::ABL1 TKI 的耐药性，且与复发性 BCR::ABL1 突变无关。值得注意的是，FLT3 BP-CML 患者的预后明显低于 FLT3- 患者。值得注意的是，我们证明，在患者来源的 FLT3 BCR::ABL1 细胞和小鼠异种移植模型中，重新利用 FLT3 抑制剂联合 BCR::ABL1 靶向治疗或单独使用 ponatinib 单一治疗可以克服耐药性并促进 BP-CML 细胞死亡。 ，我们通过 FLT3-JAK-STAT3-TAZ-TEAD-CD36 信号通路将 FLT3 重新定位为 CML 进展的关键决定因素，该信号通路可促进 TKI 耐药并预测 BP-CML 患者的预后较差。我们的研究结果开辟了新的治疗机会，利用了不同类型恶性肿瘤之间未描述的联系。© 2023。作者。

Although the development of BCR::ABL1 tyrosine kinase inhibitors (TKIs) rendered chronic myeloid leukemia (CML) a manageable condition, acquisition of drug resistance during blast phase (BP) progression remains a critical challenge. Here, we reposition FLT3, one of the most frequently mutated drivers of acute myeloid leukemia (AML), as a prognostic marker and therapeutic target of BP-CML.We generated FLT3 expressing BCR::ABL1 TKI-resistant CML cells and enrolled phase-specific CML patient cohort to obtain unpaired and paired serial specimens and verify the role of FLT3 signaling in BP-CML patients. We performed multi-omics approaches in animal and patient studies to demonstrate the clinical feasibility of FLT3 as a viable target of BP-CML by establishing the (1) molecular mechanisms of FLT3-driven drug resistance, (2) diagnostic methods of FLT3 protein expression and localization, (3) association between FLT3 signaling and CML prognosis, and (4) therapeutic strategies to tackle FLT3+ CML patients.We reposition the significance of FLT3 in the acquisition of drug resistance in BP-CML, thereby, newly classify a FLT3+ BP-CML subgroup. Mechanistically, FLT3 expression in CML cells activated the FLT3-JAK-STAT3-TAZ-TEAD-CD36 signaling pathway, which conferred resistance to a wide range of BCR::ABL1 TKIs that was independent of recurrent BCR::ABL1 mutations. Notably, FLT3+ BP-CML patients had significantly less favorable prognosis than FLT3- patients. Remarkably, we demonstrate that repurposing FLT3 inhibitors combined with BCR::ABL1 targeted therapies or the single treatment with ponatinib alone can overcome drug resistance and promote BP-CML cell death in patient-derived FLT3+ BCR::ABL1 cells and mouse xenograft models.Here, we reposition FLT3 as a critical determinant of CML progression via FLT3-JAK-STAT3-TAZ-TEAD-CD36 signaling pathway that promotes TKI resistance and predicts worse prognosis in BP-CML patients. Our findings open novel therapeutic opportunities that exploit the undescribed link between distinct types of malignancies.© 2023. The Author(s).