Akhade Vijay Suresh, Liu Tian, Docking T Roderick, Jiang Jihong, Gopal Aparna, Karsan Aly
Department of Pathology & Laboratory Medicine, University of British Columbia, G105 - 2211 Wesbrook Mall, BC V6T 2B5, Vancouver, BC, Canada.
Canada's Michael Smith Genome Sciences Centre, BC Cancer, 675 W10 Ave, BC V5Z 1L3, Vancouver, BC, Canada.
Leukemia. 2023 Apr;37(4):776-787. doi: 10.1038/s41375-023-01841-z. Epub 2023 Feb 14.
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.
我们最近描述了一种用于改善急性髓系白血病（AML）患者风险分层的16基因表达特征，称为AML预后评分（APS）。APS高风险AML患者的一个亚组显示，由蛋白酪氨酸激酶2（PTK2）基因编码的粘着斑激酶（FAK）水平升高，这与RUNX1突变相关。RUNX1突变细胞对PTK2抑制剂更敏感。由于我们无法在PTK2启动子中检测到RUNX1结合位点，我们推测RUNX1可能调节抑制PTK2的微小（mi）RNA，使得功能丧失的RUNX1突变会导致miRNA表达降低和PTK2的去抑制。对301例AML病例的配对RNA测序和miRNA测序数据进行检查，发现了两种与RUNX1表达呈正相关、在其启动子中含有RUNX1结合位点且预计靶向PTK2的miRNA。我们表明，hsa-let7a-2-3p和hsa-miR-135a-5p启动子受RUNX1调控，并且PTK2是这两种miRNA的直接靶标。即使在没有RUNX1突变的情况下，hsa-let7a-2-3p和hsa-miR-135a-5p也调节PTK2表达，并且这两种miRNA的表达降低使AML细胞对PTK2抑制敏感。这些数据解释了RUNX1如何调节PTK2，并确定了用PTK2抑制剂靶向AML的潜在miRNA生物标志物。
