CSF1R inhibitors exhibit antitumor activity in acute myeloid leukemia by blocking paracrine signals from support cells
CSF1R inhibitors exhibit antitumor activity in acute myeloid leukemia by blocking paracrine signals from support cells
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DOI：
10.1182/blood-2018-03-838946
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发表时间：
2019-02-07
期刊：
影响因子：
20.3
通讯作者：
Tyner, Jeffrey W.
中科院分区：
文献类型：
--
作者：
Edwards, David K., V;Watanabe-Smith, Kevin;Tyner, Jeffrey W.
为了确定急性髓细胞白血病（AML）的新治疗靶点，我们对原发性AML患者样本进行了小分子和小干扰RNA（siRNA）筛选。在23%的样本中，我们发现对抑制集落刺激因子1（CSF 1）受体（CSF 1 R）的敏感性，CSF 1 R是一种负责骨髓系细胞存活、增殖和分化的受体酪氨酸激酶。对CSF 1 R抑制剂GW-2580的敏感性优先见于初治和高危患者，对GW-2580的耐药与总生存期降低相关。使用流式细胞术，我们发现CSF 1 R在大多数白血病母细胞上不表达，而是在支持细胞的亚群上表达。通过质谱流式细胞术比较AML与健康供体中表达CSF 1 R的细胞，发现表达独特的细胞表面标志物。CSF 1 R表达细胞的数量与GW-2580敏感性相关。将原发性AML患者样本暴露于一组重组细胞因子显示，CSF 1 R抑制剂敏感性与对CSF 1 R配体、CSF 1和其他细胞因子（包括肝细胞生长因子（HGF））的生长反应相关。CSF 1的添加增加了AML患者样品的条件培养基中HGF和其他细胞因子的分泌，而GW-2580的添加减少了它们的分泌。在未处理的细胞中，HGF水平与GW-2580敏感性显著相关。最后，在AML患者样品中，重组HGF和HS-5条件培养基在GW-2580处理后挽救了细胞活力。我们的研究结果表明，CSF 1 R表达细胞通过分泌HGF和其他细胞因子支持大量白血病人群。这项研究确定CSF 1 R作为AML的一个新的治疗靶点，并提供了这种疾病中的旁分泌细胞因子/生长因子信号传导机制。
To identify new therapeutic targets in acute myeloid leukemia (AML), we performed small-molecule and small-interfering RNA (siRNA) screens of primary AML patient samples. In 23% of samples, we found sensitivity to inhibition of colony-stimulating factor 1 (CSF1) receptor (CSF1R), a receptor tyrosine kinase responsible for survival, proliferation, and differentiation of myeloid-lineage cells. Sensitivity to CSF1R inhibitor GW-2580 was found preferentially in de novo and favorable-risk patients, and resistance to GW-2580 was associated with reduced overall survival. Using flow cytometry, we discovered that CSF1R is not expressed on the majority of leukemic blasts but instead on a subpopulation of supportive cells. Comparison of CSF1R-expressing cells in AML vs healthy donors by mass cytometry revealed expression of unique cell-surface markers. The quantity of CSF1R-expressing cells correlated with GW-2580 sensitivity. Exposure of primary AML patient samples to a panel of recombinant cytokines revealed that CSF1R inhibitor sensitivity correlated with a growth response to CSF1R ligand, CSF1, and other cytokines, including hepatocyte growth factor (HGF). The addition of CSF1 increased the secretion of HGF and other cytokines in conditioned media from AML patient samples, whereas adding GW-2580 reduced their secretion. In untreated cells, HGF levels correlated significantly with GW-2580 sensitivity. Finally, recombinant HGF and HS-5-conditioned media rescued cell viability after GW-2580 treatment in AML patient samples. Our results suggest that CSF1R-expressing cells support the bulk leukemia population through the secretion of HGF and other cytokines. This study identifies CSF1R as a novel therapeutic target of AML and provides a mechanism of paracrine cytokine/growth factor signaling in this disease.