T-cell acute lymphoblastic leukemia (T-ALL) is a malignant hematologic disease caused by gene mutations in T-cell progenitors. As an important epigenetic regulator, PHF6 mutations frequently coexist with JAK3 mutations in T-ALL patients. However, the role(s) of PHF6 mutations in JAK3-driven leukemia remain unclear. Here, the cooperation between JAK3 activation and PHF6 inactivation is examined in leukemia patients and in mice models. We found that the average survival time is shorter in patients with JAK/STAT and PHF6 comutation than that in other patients, suggesting a potential role of PHF6 in leukemia progression. We subsequently found that Phf6 deficiency promotes JAK3^M511I-induced T-ALL progression in mice by inhibiting the Bai1-Mdm2-P53 signaling pathway, which is independent of the JAK3/STAT5 signaling pathway. Furthermore, combination therapy with a JAK3 inhibitor (tofacitinib) and a MDM2 inhibitor (idasanutlin) reduces the Phf6 KO and JAK3^M511I leukemia burden in vivo. Taken together, our study suggests that combined treatment with JAK3 and MDM2 inhibitors may potentially increase the drug benefit for T-ALL patients with PHF6 and JAK3 comutation.

T细胞急性淋巴细胞白血病（T-ALL）是一种由T细胞祖细胞基因突变引起的恶性血液病。作为重要的表观遗传调节因子，PHF6突变经常与T-ALL 患者的JAK3突变共存。然而，PHF6突变在 JAK3 驱动的白血病中的作用仍不清楚。在这里，在白血病患者和小鼠模型中检查了 JAK3 激活和 PHF6 失活之间的合作。我们发现JAK/STAT和PHF6突变患者的平均生存时间比其他患者短，这表明 PHF6 在白血病进展中的潜在作用。我们随后发现Phf6缺乏会促进JAK3 ^M511I通过抑制独立于 JAK3/STAT5 信号通路的 Bai1-Mdm2-P53 信号通路诱导小鼠 T-ALL 进展。此外，JAK3 抑制剂（托法替尼）和 MDM2 抑制剂（idasanutlin）的联合治疗可降低体内Phf6 KO 和JAK3 ^M511I白血病负担。总之，我们的研究表明 JAK3 和 MDM2 抑制剂联合治疗可能会增加PHF6和JAK3突变 T-ALL 患者的药物益处。