急性髓细胞白血病（AML）是一种异质性疾病，其特征是骨髓中髓样母细胞的克隆扩张。尽管治疗取得了进展，AML患者的预后仍然不容乐观，因此有必要寻找新的分子通路，以调控肿瘤细胞的存活和增殖。F-box泛素E3连接酶FBXO21在AML中表达较低，但其表达与AML患者以及表达水平更高的患者的生存率相关，表达水平更高的患者预后更差。在人源性AML细胞系和原发患者样本中沉默FBXO21会导致分化、抑制肿瘤进展，并增加对化疗药物的敏感性。此外，FBXO21的沉默会导致细胞因子信号通路的上调。通过对AML中FBXO21的质谱分析，我们发现FBXO21泛素化磷脂酰肌醇3激酶（PI3K）通路的一个调节亚基p85α，使其降解，从而导致PI3K信号的降低，游离p85α的二聚化和ERK的活化。这些发现揭示了泛素E3连接酶FBXO21在调控AML发病机制中起着关键作用，特别是通过调控p85α蛋白稳定性，影响PI3K的变化。© 2023年，作者们。

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by clonal expansion of myeloid blasts in the bone marrow (BM). Despite advances in therapy, the prognosis for AML patients remains poor, and there is a need to identify novel molecular pathways regulating tumor cell survival and proliferation. F-box ubiquitin E3 ligase, FBXO21, has low expression in AML, but expression correlates with survival in AML patients and patients with higher expression have poorer outcomes. Silencing FBXO21 in human-derived AML cell lines and primary patient samples leads to differentiation, inhibition of tumor progression, and sensitization to chemotherapy agents. Additionally, knockdown of FBXO21 leads to up-regulation of cytokine signaling pathways. Through a mass spectrometry-based proteomic analysis of FBXO21 in AML, we identified that FBXO21 ubiquitylates p85α, a regulatory subunit of the phosphoinositide 3-kinase (PI3K) pathway, for degradation resulting in decreased PI3K signaling, dimerization of free p85α and ERK activation. These findings reveal the ubiquitin E3 ligase, FBXO21, plays a critical role in regulating AML pathogenesis, specifically through alterations in PI3K via regulation of p85α protein stability.© 2023. The Author(s).