Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil; Department of Internal Medicine, Ribeirão Preto Medical School and Center for Cell Based Therapy, University of São Paulo, Ribeirão Preto, Brazil.
Department of Internal Medicine, Ribeirão Preto Medical School and Center for Cell Based Therapy, University of São Paulo, Ribeirão Preto, Brazil; Department of Hematology, Cancer Research Centre Groningen, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands.
Mol Cell Proteomics. 2021;20:100091. doi: 10.1016/j.mcpro.2021.100091. Epub 2021 May 7.
Non-T cell activation linker (NTAL) membrane protein depletion from lipid rafts by alkylphospholipids or downregulation by shRNA knockdown decreases cell viability through regulation of the Akt/PI3K pathway in mantle cell lymphoma and acute promyelocytic leukemia cells. Here, we confirmed that the knockdown of NTAL in acute myeloid leukemia (AML) cell lines was associated with decreased cell proliferation and survival. Similarly, a xenograft model using AML cells transduced with NTAL-shRNA and transplanted into immunodeficient mice led to a 1.8-fold decrease in tumor burden. Using immunoprecipitation, LC-MS/MS analysis, and label-free protein quantification, we identified interactors of NTAL in two AML cell lines. By evaluating the gene expression signatures of the NTAL protein interactors using the PREdiction of Clinical Outcomes from Genomic Profiles database, we found that 12 NTAL interactors could predict overall survival in AML, in at least two independent cohorts. In addition, patients with AML exhibiting a high expression of NTAL and its interactors were associated with a leukemic granulocyte-macrophage progenitor-like state. Taken together, our data provide evidence that NTAL and its protein interactors are relevant to AML cell proliferation and survival and represent potential therapeutic targets for granulocyte-macrophage progenitor-like leukemias.
非 T 细胞激活接头（NTAL）膜蛋白通过烷基磷脂从脂筏中耗竭或通过 shRNA 敲低下调会通过调节套细胞淋巴瘤和急性早幼粒细胞白血病细胞中的 Akt/PI3K 通路降低细胞活力。在这里，我们证实急性髓系白血病（AML）细胞系中 NTAL 的敲低与细胞增殖和存活减少有关。同样，使用转导了 NTAL-shRNA 的 AML 细胞并移植到免疫缺陷小鼠中的异种移植模型导致肿瘤负担减少了 1.8 倍。通过使用免疫沉淀、LC-MS/MS 分析和无标记蛋白定量，我们在两种 AML 细胞系中鉴定了 NTAL 的相互作用蛋白。通过使用基因组图谱预测临床结果数据库评估 NTAL 蛋白相互作用体的基因表达特征，我们发现 12 个 NTAL 相互作用体可以预测 AML 中的总体生存率，至少在两个独立队列中。此外，AML 患者中 NTAL 及其相互作用蛋白的高表达与白血病粒细胞-巨噬细胞祖细胞样状态相关。总之，我们的数据提供了证据，表明 NTAL 及其蛋白相互作用体与 AML 细胞的增殖和存活有关，并且代表粒细胞-巨噬细胞祖细胞样白血病的潜在治疗靶点。
