我们最近描述了一种16基因表达特征为急性髓性白血病（AML）患者改进风险分层所需的AML预后评分（APS）。一部分APS高风险AML患者显示出增加的焦点粘附激酶（FAK）水平，由蛋白酪氨酸激酶2（PTK2）基因编码，这与RUNX1突变相关。RUNX1突变细胞对PTK2抑制剂更敏感。由于我们无法检测到PTK2启动子中的RUNX1结合位点，我们假设RUNX1可能调节抑制PTK2的微(mi)RNA，这样RUNX1功能缺失的突变将导致miRNA表达减少和PTK2取消抑制。对301例AML病例的配对RNA-seq和miRNA-seq数据的检查揭示了两种miRNA，这些miRNA与RUNX1表达呈正相关，在其启动子中包含RUNX1结合位点，并预测其瞄准PTK2。我们展示了hsa-let7a-2-3p和hsa-miR-135a-5p启动子被RUNX1调节，而PTK2是这两种miRNA的直接靶标。即使没有RUNX1突变，hsa-let7a-2-3p和hsa-miR-135a-5p也可以调节PTK2表达，并且这两种miRNA的表达降低会使AML细胞对PTK2抑制剂更敏感。这些数据解释了RUNX1如何调节PTK2，并确定了用于靶向AML的PTK2抑制剂的潜在miRNA生物标志物。©2023年。作者在Springer Nature Limited的独家许可下发布。

We recently described a 16-gene expression signature for improved risk stratification of acute myeloid leukemia (AML) patients called the AML Prognostic Score (APS). A subset of APS-high-risk AML patients showed increased levels of focal adhesion kinase (FAK), encoded by the Protein Tyrosine Kinase 2 (PTK2) gene, which was correlated with RUNX1 mutations. RUNX1 mutant cells are more sensitive to PTK2 inhibitors. As we were not able to detect RUNX1-binding sites in the PTK2 promoter, we hypothesized that RUNX1 might regulate micro(mi)RNAs that repress PTK2, such that loss-of-function RUNX1 mutations would result in reduced miRNA expression and derepression of PTK2. Examination of paired RNA-seq and miRNA-seq data from 301 AML cases revealed two miRNAs that positively correlated with RUNX1 expression, contained RUNX1-binding sites in their promoters and were predicted to target PTK2. We show that the hsa-let7a-2-3p and hsa-miR-135a-5p promoters are regulated by RUNX1, and that PTK2 is a direct target of both miRNAs. Even in the absence of RUNX1 mutations, hsa-let7a-2-3p and hsa-miR-135a-5p regulate PTK2 expression, and reduced expression of these two miRNAs sensitizes AML cells to PTK2 inhibition. These data explain how RUNX1 regulates PTK2, and identify potential miRNA biomarkers for targeting AML with PTK2 inhibitors.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.