Oncogenic programs regulate the proliferation and maintenance of cancer stem cells, and can define pharmacologic dependencies. In acute myeloid leukemia (AML) with the chromosome inversion 16 (inv(16)), the fusion oncoprotein CBFβ::MYH11 regulates pathways associated with leukemia stem cell activity. Here we demonstrate that expression of Neuropilin-1 (NRP1) is regulated by the fusion oncoprotein, and promotes AML expansion. Mechanistically, we show that the NRP1 locus has open chromatin in inv(16) AML, and that CBFβ::MYH11 modulates the local function of the transcription factors ERG, GATA2 and RUNX1 to sustain NRP1 levels. We found that ERG activates NRP1 expression, and that CBFβ::MYH11 knockdown represses ERG expression, thereby allowing the repressive activity of GATA2/RUNX1 at three NRP1 enhancers. Functionally, we demonstrate that NRP1 enhances the expansion of leukemic cells in vitro and in mice, and that this activity is dependent on its VEGFR-associated FV/FVIII domain. Finally, we show that treatment with VEGF inhibitor axitinib reduces AML cell growth and delays median leukemia latency in vivo. Our findings reveal that the NRP1/VEGF axis mediates proliferation in inv(16) AML blasts, and suggest that targeting NRP1 function could be promising in combination AML therapy.

致癌程序调节癌症干细胞的增殖和维持，并且可以定义药理学依赖性。在染色体倒位 16 （inv（16）） 的急性髓性白血病 （AML） 中，融合癌蛋白 CBFβ：：MYH11 调节与白血病干细胞活性相关的通路。在这里，我们证明神经纤毛蛋白-1 （NRP1） 的表达受融合癌蛋白的调节，并促进 AML 扩增。从机制上讲，我们表明 NRP1 位点在 inv（16） AML 中具有开放染色质，并且 CBFβ：：MYH11 调节转录因子 ERG、GATA2 和 RUNX1 的局部功能以维持 NRP1 水平。我们发现 ERG 激活 NRP1 表达，CBFβ：：MYH11 敲低抑制 ERG 表达，从而允许 GATA2/RUNX1 对三个 NRP1 增强子的抑制活性。在功能上，我们证明 NRP1 在体外和小鼠中增强白血病细胞的扩增，并且这种活性取决于其 VEGFR 相关的 FV/FVIII 结构域。最后，我们表明 VEGF 抑制剂 axitinib 治疗可减少 AML 细胞生长并延迟体内中位白血病潜伏期。我们的研究结果显示，NRP1/VEGF 轴介导 inv（16） AML 原始细胞的增殖，并表明靶向 NRP1 功能在联合 AML 治疗中可能很有希望。