Investigating the role of the innate immune response in relapse or blast crisis in chronic myeloid leukemia.,Leukemia

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Investigating the role of the innate immune response in relapse or blast crisis in chronic myeloid leukemia.
Leukemia ( IF 12.8 ) Pub Date : 2020-02-20 , DOI: 10.1038/s41375-020-0771-7
Weiqi Huang _{1,

2} , Bin Liu ₁ , Elizabeth A Eklund _{1,

2}

Affiliation

Chronic myeloid leukemia (CML) is characterized by expression of the tyrosine kinase oncogene, Bcr-abl. Tyrosine kinase inhibitors (TKI) induce prolonged remission in CML, and therapy discontinuation is an accepted approach to patients with reduction in Bcr-abl transcripts of four logs or greater. Half such individuals sustain a therapy free remission, but molecular mechanisms predicting relapse are undefined. We found relative calpain inhibition in CML cells with stabilization of calpain substrates, including βcatenin and Xiap1. Since the Survivin gene is activated by βcatenin, this identified two apoptosis-resistance mechanisms. We found that Survivin impaired apoptosis in leukemia stem cells (LSCs) and Xiap1 in CML granulocytes. Consistent with this, we determined treatment with an inhibitor of Survivin, but not Xiap1, prevented relapse during TKI treatment and after therapy discontinuation in a murine CML model. By transcriptome profiling, we identified activation of innate immune response pathways in murine CML bone marrow progenitors. This was increased by TKI treatment alone, but normalized with addition of a Survivin inhibitor. We found that activation of the innate immune response induced rapid blast crisis in untreated CML mice, and chronic phase relapse during a TKI discontinuation attempt. These results suggest that extrinsic stress exerts adverse effects on CML-LSCs.

中文翻译：

研究先天性免疫应答在慢性粒细胞白血病复发或母细胞危机中的作用。

慢性粒细胞白血病（CML）的特征在于酪氨酸激酶癌基因Bcr-abl的表达。酪氨酸激酶抑制剂（TKI）导致CML的缓解时间延长，对于Bcr-abl转录水平降低四个对数或更多的患者，治疗中止是公认的方法。这些人中有一半维持无治疗的缓解，但是预测复发的分子机制尚不确定。我们发现在CML细胞中相对钙蛋白酶抑制具有稳定的钙蛋白酶底物，包括β-catenin和Xiap1。由于Survivin基因被β-catenin激活，因此确定了两种凋亡抗性机制。我们发现Survivin损害白血病干细胞（LSCs）和CML粒细胞中的Xiap1的凋亡。与此相符的是，我们确定使用Survivin抑制剂而非Xiap1进行治疗，在鼠CML模型中预防了TKI治疗期间和治疗终止后复发。通过转录组分析，我们确定了小鼠CML骨髓祖细胞中固有的免疫反应途径的激活。单独通过TKI治疗可增加这种情况，但可通过添加Survivin抑制剂使其正常化。我们发现，先天免疫应答的激活在未治疗的CML小鼠中引起快速胚细胞危机，并在TKI停用尝试期间出现慢性相复发。这些结果表明，外在压力对CML-LSC产生不利影响。但通过添加Survivin抑制剂使其标准化。我们发现，先天免疫应答的激活在未治疗的CML小鼠中引起快速胚细胞危机，并在TKI停用尝试期间出现慢性相复发。这些结果表明，外在压力对CML-LSC产生不利影响。但通过添加Survivin抑制剂使其标准化。我们发现，先天免疫应答的激活在未治疗的CML小鼠中引起快速胚细胞危机，并在TKI停用尝试期间出现慢性相复发。这些结果表明，外在压力对CML-LSC产生不利影响。

更新日期：2020-02-21

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