Hematopoietic niche drives FLT3-ITD acute myeloid leukemia resistance to quizartinib via STAT5-and hypoxia-dependent upregulation of AXL
Hematopoietic niche drives FLT3-ITD acute myeloid leukemia resistance to quizartinib via STAT5-and hypoxia-dependent upregulation of AXL
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DOI：
10.3324/haematol.2018.205385
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发表时间：
2019-09-30
期刊：
影响因子：
10.1
通讯作者：
Pasquet, Jean-Max
中科院分区：
文献类型：
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作者：
Dumas, Pierre-Yves;Naudin, Cecile;Pasquet, Jean-Max
Fms 样酪氨酸激酶 3 (FLT3-ITD) 的内部串联重复是急性髓系白血病 (AML) 中最常见的突变，与不良预后相关。 FLT3酪氨酸激酶抑制剂有望用于靶向治疗。在这里，我们研究了抑制 FLT3 抑制剂 quizartinib 反应的机制，该抑制剂是造血生态位特有的。使用 AML 原代样本和细胞系，我们证明来自造血微环境的汇聚信号通过酪氨酸激酶受体 AXL 的表达和激活驱动 FLT3-ITD 细胞对 quizartinib 的耐药性。事实上，在 quizartinib 处理的细胞中，细胞因子持续磷酸化转录因子 STAT5，从而通过直接结合其基因组序列中的保守基序来增强 AXL 表达。同样，缺氧，另一个众所周知的造血生态位标志，也增强了 AXL 的表达。最后，在异种移植小鼠模型中，AXL 的抑制显着增加了 FLT3-ITD 细胞仅在骨髓环境中对 quizartinib 的反应。这些数据强调了一种针对造血生态位的新旁路机制，该机制通过 AXL 活性的联合上调来阻碍对 quizartinib 的反应。针对这一信号传导提供了一种新疗法的前景，以根除隐藏在其特定微环境中的耐药 FLT3-ITD 白血病细胞，从而防止 FLT3-ITD 克隆复发。
Internal tandem duplication in Fms-like tyrosine kinase 3 (FLT3-ITD) is the most frequent mutation observed in acute myeloid leukemia (AML) and correlates with poor prognosis. FLT3 tyrosine kinase inhibitors are promising for targeted therapy. Here, we investigated mechanisms dampening the response to the FLT3 inhibitor quizartinib, which is specific to the hematopoietic niche. Using AML primary samples and cell lines, we demonstrate that convergent signals from the hematopoietic microenvironment drive FLT3-ITD cell resistance to quizartinib through the expression and activation of the tyrosine kinase receptor AXL. Indeed, cytokines sustained phosphorylation of the transcription factor STAT5 in quizartinib-treated cells, which enhanced AXL expression by direct binding of a conserved motif in its genomic sequence. Likewise, hypoxia, another well-known hematopoietic niche hallmark, also enhanced AXL expression. Finally, in a xenograft mouse model, inhibition of AXL significantly increased the response of FLT3-ITD cells to quizartinib exclusively within a bone marrow environment. These data highlight a new bypass mechanism specific to the hematopoietic niche that hampers the response to quizartinib through combined upregulation of AXL activity. Targeting this signaling offers the prospect of a new therapy to eradicate resistant FLT3-ITD leukemic cells hidden within their specific microenvironment, thereby preventing relapses from FLT3-ITD clones.