Hematopoietic stem and progenitor cells (HSPCs) that have impaired differentiation can transform into leukemic blasts. However, the mechanism that controls differentiation remains elusive. Here, we show that the genetic elimination of Proteinase 3 (PRTN3) in mice led to spontaneous myeloid differentiation. Mechanistically, our findings indicate that PRTN3 interacts with the N-terminal of STAT3, serving as a negative regulator of STAT3-dependent myeloid differentiation. Specifically, PRTN3 promotes STAT3 ubiquitination and degradation, while simultaneously reducing STAT3 phosphorylation and nuclear translocation during G-CSF-stimulated myeloid differentiation. Strikingly, pharmacological inhibition of STAT3 (Stattic) partially counteracted the effects of PRTN3 deficiency on myeloid differentiation. Moreover, the deficiency of PRTN3 in primary AML blasts promotes the differentiation of those cells into functional neutrophils capable of chemotaxis and phagocytosis, ultimately resulting in improved overall survival rates for recipients. These findings indicate PRTN3 exerts an inhibitory effect on STAT3-dependent myeloid differentiation and could be a promising therapeutic target for the treatment of acute myeloid leukemia.

分化受损的造血干细胞和祖细胞 (HSPC) 可转化为白血病母细胞。然而，控制分化的机制仍然难以捉摸。在这里，我们证明了小鼠中蛋白酶 3 (PRTN3) 的基因消除导致了自发的骨髓分化。从机制上讲，我们的研究结果表明 PRTN3 与 STAT3 的 N 端相互作用，作为 STAT3 依赖性骨髓分化的负调节因子。具体而言，PRTN3 促进 STAT3 泛素化和降解，同时在 G-CSF 刺激的骨髓分化过程中减少 STAT3 磷酸化和核转位。引人注目的是，STAT3 (Stattic) 的药理学抑制部分抵消了 PRTN3 缺乏对骨髓分化的影响。此外，原发性 AML 母细胞中 PRTN3 的缺乏会促进这些细胞分化为具有趋化性和吞噬作用的功能性中性粒细胞，最终提高受体的总体存活率。这些发现表明 PRTN3 对 STAT3 依赖性骨髓分化具有抑制作用，可能成为治疗急性髓系白血病的一个有前途的治疗靶点。