抑制性磷酸酶，如肌醇 5 磷酸酶 SHIP1 可能会提高自身免疫检查点激活的阈值，从而使具有强致癌 B 细胞受体信号传导的恶性细胞能够潜在地导致 B 细胞急性淋巴细胞白血病 (B-ALL)。逃避负面选择。在这里，我们表明 SHIP1 在 B-ALL 亚型中表达存在差异，并且 SHIP1 表达的高与低与特定的 B-ALL 亚型相关。特别是，我们在费城染色体 (Ph) 阳性和 ETV6-RUNX1 重排的 B-ALL 细胞中发现 SHIP1 高表达。通过 RNA 干扰靶向敲低 SHIP1 证明，B-ALL 细胞的体外增殖及其体内致瘤性扩散部分取决于 SHIP1 表达。我们研究了 B 细胞特异性转录因子 Ikaros 对 SHIP1（作为 AKT 信号通路的重要拮抗剂）的调节。 Ikaros 的靶向恢复和拮抗酪蛋白激酶 2 的药理抑制导致 SHIP1 表达大幅减少，同时显着抑制 AKT 激活和细胞生长。重要的是，Ikaros 的肿瘤抑制功能通过 SHIP1 依赖性累加效应得到增强。此外，我们的研究表明，所有三种 AKT 亚型都有助于 B-ALL 细胞中的促有丝分裂和抗凋亡信号传导。相反，单一 AKT 同工型的过度激活足以通过增加氧化应激诱导负选择。总之，我们的研究证明了 Ikaros 对 B-ALL 中 SHIP1 表达的调节功能，并强调了持续 SHIP1 表达与防止 PI3K/AKT/mTOR 信号过度激活的细胞经历负选择的相关性。© 2024。作者。

Inhibitory phosphatases, such as the inositol-5-phosphatase SHIP1 could potentially contribute to B-cell acute lymphoblastic leukemia (B-ALL) by raising the threshold for activation of the autoimmunity checkpoint, allowing malignant cells with strong oncogenic B-cell receptor signaling to escape negative selection. Here, we show that SHIP1 is differentially expressed across B-ALL subtypes and that high versus low SHIP1 expression is associated with specific B-ALL subgroups. In particular, we found high SHIP1 expression in both, Philadelphia chromosome (Ph)-positive and ETV6-RUNX1-rearranged B-ALL cells. As demonstrated by targeted knockdown of SHIP1 by RNA interference, proliferation of B-ALL cells in vitro and their tumorigenic spread in vivo depended in part on SHIP1 expression. We investigated the regulation of SHIP1, as an important antagonist of the AKT signaling pathway, by the B-cell-specific transcription factor Ikaros. Targeted restoration of Ikaros and pharmacological inhibition of the antagonistic casein kinase 2, led to a strong reduction in SHIP1 expression and at the same time to a significant inhibition of AKT activation and cell growth. Importantly, the tumor suppressive function of Ikaros was enhanced by a SHIP1-dependent additive effect. Furthermore, our study shows that all three AKT isoforms contribute to the pro-mitogenic and anti-apoptotic signaling in B-ALL cells. Conversely, hyperactivation of a single AKT isoform is sufficient to induce negative selection by increased oxidative stress. In summary, our study demonstrates the regulatory function of Ikaros on SHIP1 expression in B-ALL and highlights the relevance of sustained SHIP1 expression to prevent cells with hyperactivated PI3K/AKT/mTOR signaling from undergoing negative selection.© 2024. The Author(s).