Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML.
Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML.
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DOI：
10.1056/nejmoa1214514
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发表时间：
2013-05-09
期刊：
影响因子：
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通讯作者：
Tyner JW
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文献类型：
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作者：
Maxson JE;Gotlib J;Pollyea DA;Fleischman AG;Agarwal A;Eide CA;Bottomly D;Wilmot B;McWeeney SK;Tognon CE;Pond JB;Collins RH;Goueli B;Oh ST;Deininger MW;Chang BH;Loriaux MM;Druker BJ;Tyner JW
许多血液系统癌症的分子原因仍不清楚。这些癌症包括慢性嗜中性粒细胞白血病（CNL）和非典型（BCR-ABL 1阴性）慢性髓性白血病（CML），这两种癌症都是基于粒细胞的肿瘤性扩增和排除已知在其他骨髓增生性肿瘤和骨髓增生性-骨髓增生异常重叠肿瘤中发生的遗传驱动因素而诊断的。为了确定这些疾病中潜在的遗传驱动因素，我们使用了深度测序的综合方法，结合对从CNL或非典型CML患者中获得的原代白血病细胞进行酪氨酸激酶特异性小干扰RNA或小分子激酶抑制剂的筛选。我们使用体外转化试验验证了候选癌基因，并使用原代细胞集落试验验证了药物敏感性。我们在27例CNL或非典型CML患者中的16例（59%）中发现了编码集落刺激因子3受体（CSF 3R）的基因的激活突变。这些突变在CSF 3R的两个不同区域内分离，并导致通过SRC家族-TNK 2或JAK激酶的优先下游激酶信号传导和对激酶抑制剂的差异敏感性。一名携带JAK激活CSF 3R突变的CNL患者在给予JAK 1/2抑制剂ruxolitinib后临床症状明显改善。CSF 3R突变在CNL或非典型CML患者中很常见，并代表了诊断这些肿瘤的潜在有用标准。（由白血病和淋巴瘤协会和其他人资助。
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. 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. We identified activating mutations in the gene encoding the receptor for colonystimulating 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. 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.)