Myelodysplastic syndrome with concomitant del(5q) and JAK2 V617F mutation transformed to acute myeloid leukemia with an additional chromosomal abnormality after a long-term treatment with lenalidomide
Myelodysplastic syndrome with concomitant del(5q) and JAK2 V617F mutation transformed to acute myeloid leukemia with an additional chromosomal abnormality after a long-term treatment with lenalidomide
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伴有 del(5q) 和 JAK2 V617F 突变的骨髓增生异常综合征在长期接受来那度胺治疗后转化为急性髓系白血病并伴有额外的染色体异常
DOI：
10.1080/10428194.2017.1295146
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发表时间：
2017
影响因子：
2.6
通讯作者：
M. Nohgawa
中科院分区：
文献类型：
--
作者：
S. Oka;K. Ono;M. Nohgawa
染色体5 q间质缺失（del（5 q））是骨髓增生异常综合征（MDS）最常见的细胞遗传学异常。一部分孤立性del（5 q）患者具有独特的血液学和病理学特征，被称为“5 q综合征”[1]。5 q综合征患者有难治性大红细胞性贫血、血小板计数增加或正常、轻度白细胞减少、巨核细胞发育不良和无痛性临床病程。涉及Janus激酶-2（JAK 2 V617 F）的跨膜调节结构域的V617 F突变是在经典骨髓增生性肿瘤（MPN）中检测到的最常见遗传异常[2]。这种突变导致促红细胞生成素受体的组成性激活，并解释了真性红细胞增多症患者内源性红细胞集落的生长。最近报告了携带JAK 2 V617 F突变的孤立del（5 q）MDS患者，来那度胺治疗可能对这些患者有益且有效[3-6]。然而，长期的不适仍然是未知的，这种药物在这些条件下的作用机制尚未详细阐明，需要建立安全的治疗持续时间和停药时间。一名73岁女性于2008年12月因重度大红细胞性贫血和血小板增多症（血红蛋白53 g/l，血小板667 10/l，白色血细胞计数5.7 10/l）转诊至我院。中性粒细胞为3.99 10/l，嗜酸性粒细胞为0.22 10/l，单核细胞为0.11 10/l，淋巴细胞为1.36 10/l。外周血中不存在原始细胞。未检测到脾或肝肿大。骨髓穿刺显示细胞结构增加，伴红系发育不全;髓系增生，左移，巨核细胞数量增加，大小减小，细胞核小叶减少，同时还观察到小巨核细胞（图1（a））。原始细胞<1%，并且通过Perls染色证明没有环形铁粒幼细胞。TP 53突变与p53过表达有关[7]，并且在2%的造血细胞中发现了强的核p53免疫染色（图1（B）），而在少数造血细胞中观察到CD 34免疫染色。在20个中期分裂相中观察到异常核型，显示5号染色体长臂缺失[46，XX，del（5 q）（q13 q31）（18/20细胞），46，XX（2/20细胞）]。FISH分析显示74%的细胞核中存在5 q31。分子生物学分析显示BCR/ABL重排为阴性，定量RT-PCR检测到JAK 2 V617 F突变（20%）。因此，根据WHO血液学肿瘤分类[8]，患者被诊断为MDS伴5 q染色体孤立缺失和伴随JAK 2 V617 F突变，根据国际预后评分系统（IPSS）将其归类为低风险组[9]。在明确诊断的基础上，开始给予来那度胺10 mg每日一次，共21天，28天为一个周期，因为患者依赖输血。在治疗的第一个月内，患者变得不依赖输血。治疗3个月后，患者外周血计数正常，重复骨髓检查显示骨髓细胞轻度增多。核型异常已完全解决，显示一个正常的女性核型和FISH分析检测5 q31在0%的细胞核。此外，分子分析对JAK 2 V617 F突变呈阴性。她愿意继续来那度胺治疗，并在随后的几个月内保持完全细胞遗传学缓解（CCyR）、分子学缓解和输血依赖性。在治疗开始后84个月，血液学值基本保持正常，骨髓中未出现原始细胞增加。然而，核型分析显示5号染色体长臂缺失[46，XX，del（5 q）（q13 q31）（1/20细胞），46，XX（19/20细胞）]，FISH分析显示10%的细胞核中存在5 q31。此外，JAK 2 V617 F突变的分子分析呈阳性（13%）。患者出现
The interstitial deletion of chromosome 5q (del(5q)) is the most common cytogenetic abnormality in myelodysplastic syndromes (MDS). A subset of patients with isolated del(5q) have distinct hematological and pathological features, recognized as the ‘5q-syndrome’ [1]. Patients with 5q-syndrome have refractory macrocytic anemia, an increased or normal platelet count, mild leukopenia, dysplastic megakaryocytes, and an indolent clinical course. The V617F mutation involving the juxtamembrane regulatory domain of Janus kinase-2 (JAK2 V617F) is the most common genetic abnormality detected in classical myeloproliferative neoplasms (MPN) [2]. This mutation results in the constitutive activation of the erythropoietin receptor and accounts for the growth of endogenous erythroid colonies in patients with polycythemia vera. Patients with isolated del(5q) MDS harboring the JAK2 V617F mutation have recently been reported, with lenalidomide treatments potentially being beneficial and effective for these patients [3–6]. However, long-term prognoses remain unknown, and the mechanism of action of this drug under these conditions has not yet been elucidated in detail, and safe treatment durations and discontinuation times need to be established. A 73-year-old female was referred to our hospital in December 2008 with severe macrocytic anemia and thrombocytosis (hemoglobin 53 g/l, platelets 667 10/l, and white blood count 5.7 10/l). Neutrophils were 3.99 10/l, eosinophils 0.22 10/l, monocytes 0.11 10/l, and lymphocytes 1.36 10/l. No blasts were present in peripheral blood. Neither splenonor hepatomegaly was detected. A bone marrow aspirate revealed increased cellularity with concomitant hypoplasia of the erythroid lineage; the myeloid lineage was hyperplastic with a left shift and megakaryocytes had increased in number, decreased in size, and their nuclei were hypolobulated, while micromegakaryocytes were also observed (Figure 1(a)). Blasts were <1%, and no ring sideroblasts were evidenced by Perls' staining. TP53 mutation is linked to p53 overexpression [7] and strong nuclear p53 immunostaining was found in 2% of hematopoietic cells (Figure 1(b)), while CD34 immunostaining was noted in a few hematopoietic cells. An abnormal karyotype was observed in 20 metaphases that showed the deletion of the long arm of chromosome 5 [46, XX, del(5q)(q13q31) (18/20 cells), 46, XX (2/20 cells)]. A FISH analysis revealed 5q31 in 74% of nuclei. On molecular analyses, the BCR/ABL rearrangement was negative and JAK2 V617F mutation was identified (20%) by quantitative RT-PCR. Therefore, based on the WHO classification of hematological neoplasms [8], the patient was diagnosed with MDS with the isolated deletion of the 5q chromosome and concomitant JAK2 V617F mutation, categorizing her to the low risk group according to the International Prognostic Scoring System (IPSS) [9]. On the basis of a definite diagnosis, the administration of 10mg lenalidomide daily for 21 days in a 28-day-cycle was initiated because the patient was transfusiondependent. Within the first month of the treatment, the patient became transfusion-independent. After 3 months of the treatment, she achieved normal peripheral blood counts, and a repeat marrow examination showed slightly hypercellular marrow. Karyotypic abnormalities had completely resolved to show a normal female karyotype and a FISH analysis detected 5q31 in 0% of nuclei. Additionally, molecular analyses were negative for the JAK2 V617F mutation. She was willing to continue the lenalidomide treatment, and maintained the complete cytogenetic response (CCyR), molecular response, and transfusion-independency during the following months. At 84 months post-treatment initiation, hematological values remained substantially normal, and no blast increased in the bone marrow. However, karyotypic analyses showed the deletion of the long arm of chromosome 5 [46, XX, del(5q)(q13q31) (1/20 cells), 46, XX (19/20 cells)], and a FISH analysis revealed 5q31 in 10% of nuclei. Additionally, molecular analyses were positive for the JAK2 V617F mutation (13%). The patient showed