B‐CLL developing in a patient with PV is not affected by V617F mutation of the Janus kinase 2
B‐CLL developing in a patient with PV is not affected by V617F mutation of the Janus kinase 2
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PV 患者中发生的 B-CLL 不受 Janus 激酶 2 V617F 突变的影响
DOI：
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发表时间：
2006
影响因子：
3.1
通讯作者：
H. Kreipe
中科院分区：
文献类型：
--
作者：
K. Hussein;K. Brakensiek;M. Ballmaier;M. Bormann;G. Göhring;T. Buhr;O. Bock;H. Kreipe
致编辑：我们提出的情况下，79岁的白人男性真性红细胞增多症（PV）和罕见的B细胞慢性淋巴细胞白血病（B-CLL）的并发症。20世纪80年代报告了少数PV和BCLL病例（1-7），但除了以费城染色体为特征的慢性髓性白血病（CML）外，之前尚未研究慢性骨髓增生性疾病（CMPD）和淋巴增生性恶性肿瘤是否与克隆相关（8）。最近在CMPD中发现的Janus激酶2（JAK 2）功能获得性点突变（1849 G>T/V617 F）使得能够进行谱系参与分析（9-11），以阐明来自异常造血干细胞（HSC）的共同起源。事实上，少数PV病例不仅在HSC和髓样细胞中，而且在淋巴样细胞中显示JAK 2克隆性（12）。这些发现是否对淋巴组织增生性疾病的发展有任何影响是一个有争议的问题，因为据报道B-CLL和其他淋巴肿瘤没有携带突变（10）。在临床上，在根据WHO标准进行骨髓检查确认诊断之前，患者的PV已知6年，但另外在组织学上鉴定出B-CLL，其揭示了CD 23免疫表型（图1A，B）。外周血的流式细胞术导致检测到12.9%的白血病B细胞，其特征为κ、CD 19、CD 5、CD 20、CD 22、CD 23、人白细胞抗原（HLA）-DR、CD 25和CD 38，但仅检测到0.1%的规则分化的B淋巴细胞。通过分离的B细胞组分的荧光原位杂交（FISH），未检测到B-CLL典型的12三体，11q22.3，13 q14和17 p13缺失（13）。体格检查显示脾脏肿大，双侧手掌红细胞增多，泌尿系检查显示促红细胞生成素水平降低（2.5 U/L），红细胞计数升高（6.7 · 10/L），高血红蛋白（16.3 g/dL）和红细胞压积（50%），平均红细胞血红蛋白（MCH）水平降低（24.2 pg），平均小体体积（MCV）（75.7 fL）和平均红细胞血红蛋白浓度（MCHC）（32.0 g/dL），白细胞增多（18.7 · 10/L），淋巴细胞9%，髓细胞1%，血小板增多（621 · 10/L）。治疗以间歇性放血、抗凝剂和抗凝剂为主。通过焦磷酸测序（11）对单核血细胞（28.3%）和福尔马林固定石蜡包埋（FFPE）骨髓细胞（25.7%）进行突变T等位基因的定量。纯化的粒细胞（51.1%）和激光显微切割的巨核细胞（52.5%）代表PV克隆，而在CD 19/CD 5白血病B细胞、CD 19/CD 5 B和CD 3 T淋巴细胞中检测到100%野生型JAK 2。通过BsaXI限制性分析进一步证实突变状态（14）（图1B，C）。由于缺乏典型的B-CLL畸变和X染色体失活试验在这种情况下的不可行性，我们不能排除两种恶性肿瘤共享JAK 2异常HSC以及JAK 2发生在克隆性造血的背景下（15）。然而，尽管淋巴细胞在PV患者中显示JAK 2（12），但在我们的病例中，B-CLL的发展不受潜在PV JAK 2克隆的影响。据推测，该突变是CMPD发展的有利因素，但对淋巴组织增生性肿瘤发生是不利因素。因此，我们得出结论，PV和B-CLL的发生在这个病人代表两个独立的肿瘤的髓系和淋巴系，不共享一个共同的JAK 2前体细胞。Eur J Haematol 2006：77：539-541 doi：10.1111/j.0902-4441.2006.t01-1-EJH2940.x保留所有权利2006 The Authors Journal compilation 2006 Blackwell Munksgaard
To the Editor: We present the case of a 79-year-old Caucasian male with polycythemia vera (PV) and the rare concomitant occurrence of B-cell chronic lymphocytic leukaemia (B-CLL). A few cases of PV and BCLL were reported in the 1980s (1–7), but with the exception of chronic myeloid leukaemia (CML), which is characterised by the Philadelphia chromosome, it has not been studied before whether chronic myeloproliferative disorders (CMPD) and lymphoproliferative malignancies are clonally related (8). The recently discovered Janus kinase 2 (JAK2) gain-of-function point mutation (1849G>T/V617F) in CMPDs enables a lineageinvolvement analysis (9–11), in order to elucidate a common origin from an aberrant haematopoietic stem cell (HSC). Indeed, a minority of PV cases showed the JAK2 clonality not only in HSC and myeloid cells but also in lymphoid cells (12). Whether these findings have any implication on the development of lymphoproliferative disorders is a matter of debate, because B-CLL and other lymphoid neoplasms were reported not to harbour the mutation (10). Clinically, the patient’s PV was known for 6 yr, before examination of the bone marrow confirmed the diagnosis according to WHO criteria, but additionally B-CLL was histologically identified, which revealed a CD23 immunophenotype (Fig. 1A, B). Flow cytometry of peripheral blood led to the detection of 12.9% leukaemic B cells characterised by kappa, CD19, CD5, CD20, CD22, CD23, human leucocyte antigen (HLA)-DR, CD25 and CD38, but only 0.1% regular differentiated B lymphocytes. B-CLLtypical trisomy 12, deletion of 11q22.3, 13q14 and 17p13 (13) were not detectable by fluorescent in situ hybridisation (FISH) of the isolated B-cell fraction. Physical examination revealed spleen enlargement andpalmarerythemaonbothsides.Laboratoryexaminations showed low erythropoietin level (2.5 U/L), elevated erythrocyte count (6.7 · 10/L), high haemoglobin (16.3 g/dL) and haematocrit (50%) with lowered levels of Mean Corpuscular Haemoglobin (MCH) (24.2 pg),MeanCorpuscularVolume (MCV) (75.7 fL) and Mean Corpuscular Haemoglobin Concentration (MCHC) (32.0 g/dL), leucocytosis (18.7 · 10/L) with 9% lymphocytes and 1% myelocytes and thrombocytosis (621 · 10/L). Therapy was based on intermittent phlebotomy, anticoagulants and analgetics. Quantification of the mutated T allele by pyrosequencing (11) was performed on mononuclear blood cells (28.3%) and formalin-fixed paraffinembedded (FFPE) bone marrow cells (25.7%). Purified granulocytes (51.1%) and laser-microdissected megakaryocytes (52.5%) represented the PV clone, whereas 100% wild-type JAK2 was detected in CD19/CD5 leukaemic B cells, CD19/CD5 B and CD3 T lymphocytes. The mutation status was further confirmed by BsaXI restriction analysis (14) (Fig. 1B, C). As a result of the lack of typical B-CLL aberrations and the unfeasibility of an X-chromosome inactivation assay in this case, we cannot rule out that both malignancies share a JAK2 aberrant HSC and that JAK2 occurred on the background of clonal haematopoiesis (15). However, although lymphocytes were reported to display JAK2 in PV patients (12), in our case the development of B-CLL was not affected by the underlying PV JAK2 clone. Presumably, the mutation is an advantage for CMPD development, but an unfavourable factor for lymphoproliferative tumorigenesis. Therefore, we conclude that the occurrence of PV and B-CLL in this patient represents two separate neoplasms of the myeloid and lymphoid lineage, which do not share a common JAK2 precursor cell. Eur J Haematol 2006: 77: 539–541 doi:10.1111/j.0902-4441.2006.t01-1-EJH2940.x All rights reserved 2006 The Authors Journal compilation 2006 Blackwell Munksgaard
影响因子：
20.3
作者：
Levine, RL;Loriaux, M;Deininger, MWN
通讯作者：
Deininger, MWN
影响因子：
20.3
作者：
Jelinek, J;Oki, Y;Issa, JPJ
通讯作者：
Issa, JPJ