Institute of Biochemistry and Signal Transduction, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
Research Institute Children's Cancer Center Hamburg, Hamburg and Department of Pediatric Oncology and Hematology, University Medical Center, 20246 Hamburg, Germany.
Cells. 2023 Jul 6;12(13):1798. doi: 10.3390/cells12131798.
Acute lymphoblastic leukemia (ALL) is the most common cause of cancer-related death in children. Despite significantly increased chances of cure, especially for high-risk ALL patients, it still represents a poor prognosis for a substantial fraction of patients. Misregulated proteins in central switching points of the cellular signaling pathways represent potentially important therapeutic targets. Recently, the inositol phosphatase SHIP1 (SH2-containing inositol 5-phosphatase) has been considered as a tumor suppressor in leukemia. SHIP1 serves as an important negative regulator of the PI3K/AKT signaling pathway, which is frequently constitutively activated in primary T-ALL. In contrast to other reports, we show for the first time that SHIP1 has not been lost in T-ALL cells, but is strongly downregulated. Reduced expression of SHIP1 leads to an increased activation of the PI3K/AKT signaling pathway. SHIP1-mRNA expression is frequently reduced in primary T-ALL samples, which is recapitulated by the decrease in SHIP1 expression at the protein level in seven out of eight available T-ALL patient samples. In addition, we investigated the change in the activity profile of tyrosine and serine/threonine kinases after the restoration of SHIP1 expression in Jurkat T-ALL cells. The tyrosine kinase receptor subfamilies of NTRK and PDGFR, which are upregulated in T-ALL subgroups with low SHIP1 expression, are significantly disabled after SHIP1 reconstitution. Lentiviral-mediated reconstitution of SHIP1 expression in Jurkat cells points to a decreased cellular proliferation upon transplantation into NSG mice in comparison to the control cohort. Together, our findings will help to elucidate the complex network of cell signaling proteins, further support a functional role for SHIP1 as tumor suppressor in T-ALL and, much more importantly, show that full-length SHIP1 is expressed in T-ALL samples.
急性淋巴细胞白血病（ALL）是儿童癌症相关死亡的最常见原因。尽管高风险 ALL 患者的治愈率显著提高，但对于相当一部分患者来说，预后仍然较差。细胞信号通路的中央开关点的失调蛋白代表潜在的重要治疗靶点。最近，肌醇磷酸酶 SHIP1（含 SH2 的肌醇 5-磷酸酶）已被认为是白血病的肿瘤抑制因子。SHIP1 作为 PI3K/AKT 信号通路的重要负调控因子，该通路在原发性 T-ALL 中经常持续激活。与其他报道相反，我们首次表明 SHIP1 并未在 T-ALL 细胞中丢失，而是被强烈下调。SHIP1 表达的降低导致 PI3K/AKT 信号通路的激活增加。SHIP1-mRNA 在原发性 T-ALL 样本中表达频率降低，在八个可获得的 T-ALL 患者样本中的七个样本中，SHIP1 表达水平的降低也证实了这一点。此外，我们还研究了在 Jurkat T-ALL 细胞中恢复 SHIP1 表达后酪氨酸和丝氨酸/苏氨酸激酶活性谱的变化。SHIP1 低表达的 T-ALL 亚组中上调的 NTRK 和 PDGFR 酪氨酸激酶受体亚家族在 SHIP1 重建后显著失活。与对照组相比，Jurkat 细胞中慢病毒介导的 SHIP1 表达重建后，在移植到 NSG 小鼠中时细胞增殖减少。总之，我们的研究结果将有助于阐明细胞信号蛋白的复杂网络，进一步支持 SHIP1 在 T-ALL 中作为肿瘤抑制因子的功能作用，更重要的是，表明全长 SHIP1 在 T-ALL 样本中表达。
