NEJM：基因检测有助于白血病靶向治疗

　　《新英格兰医学杂志》5月8日在线发表的一项研究显示，集落刺激因子3(CSF3R)基因的致癌基因突变是慢性中性粒细胞白血病(CNL)和不典型慢性髓系白血病(CML)的决定性分子异常。检测这些突变不仅有助于诊断这两种罕见疾病，而且有助于评估以中性粒细胞增多为特征的病因不明的其他疾病。此外，基因检测还有助于改进骨髓增殖性肿瘤的分子分类。

　　在这项研究中，波特兰俄勒冈健康与科学大学血液与肿瘤系的Julia E. Maxson博士及其同事对27例患有CNL或不典型CML的患者及超过300例患有其他血癌(包括急性髓系白血病、T细胞急性淋巴母细胞白血病和B细胞急性淋巴母细胞白血病)的患者的细胞样本进行了筛查，并对来自1,862个候选基因的已知参与癌症信号传导的区域(如与激酶、磷酸酶、非激酶生长因子或细胞因子受体相关的区域)进行测序。

　　结果显示，27例CNL或不典型CML患者中有16例(59%)检出某些新的CSF3R突变，这些突变在其他研究对象中的检出率不到1%，表明这些CSF3R突变为这两种疾病所特有。研究者表示，既往未发现这两种疾病的其他特异性遗传标志物。

　　研究者随后评估了携带CSF3R突变的样本是否对化学激酶抑制剂或针对激酶的小干扰RNA敏感。结果显示一类突变(截断CSF3R胞质尾的移码或无义突变)对多激酶抑制剂达沙替尼敏感，另一类突变(近膜突变)仅对靶向JAK家族激酶的抑制剂(如鲁索利替尼)敏感。体外集落形成试验证实，这两类突变具有不同的转换能力，并且两者对不同的药物敏感。

　　1例携带CSF3R近膜突变的CNL患者的细胞在体外对鲁索利替尼敏感。给予该患者口服鲁索利替尼10 mg、2次/d，结果白细胞和中性粒细胞绝对计数明显降低。将剂量增至15 mg、2次/d后，白细胞和中性粒细胞绝对计数进一步降低，并且血小板计数复常。研究者表示，有必要进一步研究酪氨酸激酶抑制剂对携带CSF3R突变的中性粒细胞白血病患者的治疗潜力。这些CSF3R突变定义了一个新的血癌分子子集，并且为开发新治疗方法指明了方向。

与白血病相关的拓展阅读：

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Oncogenic CSF3R Mutations in Chronic Neutrophilic Leukemia and Atypical CML
Background
The molecular causes of many hematologic cancers remain unclear. Among these cancers are chronic neutrophilic leukemia (CNL) and atypical (BCR-ABL1–negative) chronic myeloid leukemia (CML), both of which are diagnosed on the basis of neoplastic expansion of granulocytic cells and exclusion of genetic drivers that are known to occur in other myeloproliferative neoplasms and myeloproliferative–myelodysplastic overlap neoplasms.
Methods
To identify potential genetic drivers in these disorders, we used an integrated approach of deep sequencing coupled with the screening of primary leukemia cells obtained from patients with CNL or atypical CML against panels of tyrosine kinase–specific small interfering RNAs or small-molecule kinase inhibitors. We validated candidate oncogenes using in vitro transformation assays, and drug sensitivities were validated with the use of assays of primary-cell colonies.
Results
We identified activating mutations in the gene encoding the receptor for colony-stimulating factor 3 (CSF3R) in 16 of 27 patients (59%) with CNL or atypical CML. These mutations segregate within two distinct regions of CSF3R and lead to preferential downstream kinase signaling through SRC family–TNK2 or JAK kinases and differential sensitivity to kinase inhibitors. A patient with CNL carrying a JAK-activating CSF3R mutation had marked clinical improvement after the administration of the JAK1/2 inhibitor ruxolitinib.
Conclusions
Mutations in CSF3R are common in patients with CNL or atypical CML and represent a potentially useful criterion for diagnosing these neoplasms. (Funded by the Leukemia and Lymphoma Society and others.)