Chronic neutrophilic leukemia: novel mutations and their impact on clinical practice
Chronic neutrophilic leukemia: novel mutations and their impact on clinical practice
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DOI：
10.1097/moh.0000000000000114
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发表时间：
2015-03
影响因子：
3.2
通讯作者：
A. Tefferi;M. Elliott;A. Pardanani
中科院分区：
文献类型：
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作者：
A. Tefferi;M. Elliott;A. Pardanani
综述目的：慢性嗜中性粒细胞白血病（CNL）是一种罕见的BCR-ABL 1阴性髓系恶性肿瘤，其特征是成熟的粒细胞增多而无粒细胞生成障碍。CNL的鉴别诊断包括反应性或继发性粒细胞增多症和其他髓系肿瘤，如非典型慢性髓系白血病（aCML）和慢性粒单核细胞白血病（CMML）。在此，我们关注最近描述的CNL突变及其对诊断、预后和治疗的影响。2013年，在CNL和aCML中描述了近膜CSF 3R突变，最常见的是CSF 3RT 618 I。随后的研究证实，几乎所有CNL患者都存在这种突变，但aCML患者没有。此外，大多数CSF 3R突变的CNL患者还表达了其他突变，如SETBP 1和ASXL 1，这可能是有害的。实验室研究表明，CSF 3RT 618 I诱导小鼠JAK-STAT和CNL样疾病的JAK抑制剂敏感性激活。病例报告表明JAK抑制剂治疗CSF 3R突变的CNL具有缓解活性，但无疾病修饰活性。CNL现在是一种形态学和分子学定义的髓系恶性肿瘤，不再是一种排除性诊断。CNL特异性分子标志物的鉴定提供了急需的发病机理见解，也提供了修改当前诊断标准和鉴定预后生物标志物和潜在药物靶点的机会。
Purpose of reviewChronic neutrophilic leukemia (CNL) is a rare BCR-ABL1-negative myeloid malignancy that is characterized by mature granulocytosis without dysgranulopoiesis. Differential diagnosis of CNL includes reactive or secondary granulocytosis and other myeloid neoplasms, such as atypical chronic myeloid leukemia (aCML) and chronic myelomonocytic leukemia (CMML). Herein, we focus on recently described mutations in CNL and their impact on diagnosis, prognosis and treatment. Recent findingsIn 2013, membrane-proximal CSF3R mutations, most frequently CSF3RT618I, were described in CNL and aCML. Subsequent studies confirmed the presence of such mutations in nearly all patients with CNL but not in aCML. Furthermore, the majority of the patients with CSF3R-mutated CNL also expressed other mutations, such as SETBP1 and ASXL1, which might be prognostically detrimental. Laboratory studies revealed that CSF3RT618I induced JAK inhibitor-sensitive activation of JAK-STAT and CNL-like disease in mice. Case reports have indicated palliative but not disease-modifying activity of JAK inhibitor therapy in CSF3R-mutated CNL. SummaryCNL is now a morphologically and molecularly defined myeloid malignancy, and no longer a diagnosis of exclusion. The identification of CNL-specific molecular markers provides a much needed pathogenetic insight and also offers the opportunity to revise current diagnostic criteria and identify prognostic biomarkers and potential drug targets.