MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia.
MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia.
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DOI：
10.1371/journal.pmed.0030270
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发表时间：
2006-07
期刊：
影响因子：
15.8
通讯作者：
Levine, Ross L.
中科院分区：
文献类型：
--
作者：
Pikman, Yana;Lee, Benjamin H.;Mercher, Thomas;McDowell, Elizabeth;Ebert, Benjamin L.;Gozo, Maricel;Cuker, Adam;Wernig, Gerlinde;Moore, Sandra;Galinsky, Ilene;DeAngelo, Daniel J.;Clark, Jennifer J.;Lee, Stephanie J.;Golub, Todd R.;Wadleigh, Martha;Gilliland, D. Gary;Levine, Ross L.
最近在真性红细胞增多症 (PV)、原发性血小板增多症 (ET) 和骨髓纤维化伴骨髓化生 (MF) 患者中发现了 JAK2V617F 等位基因。随后的分析表明，JAK-STAT 信号转导途径的组成性激活是这些患者的重要发病事件，并且 JAK2V617F 的酶抑制可能在这种情况下具有治疗益处。然而，相当一部分 ET 或 MF 患者是 JAK2V617F 阴性。我们假设 JAK-STAT 通路的激活也可能是由于某些造血特异性细胞因子受体（包括促红细胞生成素受体（EPOR）、血小板生成素受体（MPL）或粒细胞集落刺激因子受体（GCSFR））激活突变的结果而发生。 对编码 EPOR、MPL 和 GCSFR 的跨膜结构域和近膜结构域的外显子进行 DNA 序列分析，并与口腔拭子中的种系 DNA 进行比较，发现在 9% (4/45) 的 JAKV617F 阴性 MF 中，MPL 跨膜结构域 (W515L) 存在体细胞激活突变。 MPLW515L 在 32D、UT7 或 Ba/F3 细胞中的表达赋予细胞因子非依赖性生长和血小板生成素超敏性，并导致 JAK2、STAT3、STAT5、AKT 和 ERK 的组成型磷酸化。此外，小分子 JAK 激酶抑制剂在体外抑制 MPLW515L 介导的增殖和 JAK-STAT 信号传导。在小鼠骨髓移植试验中，MPLW515L（而非野生型 MPL）的表达导致完全渗透性骨髓增殖性疾病，其特征是明显的血小板增多（Plt 计数 1.9–4.0 × 10 12/L）、由于髓外造血导致的明显脾肿大以及网状蛋白纤维化增加。 通过 MPLW515L 激活 JAK-STAT 信号传导是 JAK2V617F 阴性 MF 患者的重要致病事件。 MPLW515L 介导的骨髓增殖性疾病 (MPD) 的骨髓移植模型表现出人类 MF 的某些特征，包括髓外造血、脾肿大和巨核细胞增殖。在 JAK2V617F 阴性 MPD 中，有必要进一步分析 JAK-STAT 通路的正负调节因子。 骨髓纤维化伴骨髓化生 (MF) 是一组慢性血液疾病之一，称为慢性骨髓增殖性疾病。这些疾病有时会变成急性白血病。骨髓纤维化的主要异常是骨髓充满纤维（疤痕）组织（因此称为骨髓纤维化），从而阻止其有效产生正常血细胞。此外，残留的白细胞是异常的（即化生的）。这些异常的临床影响是患者贫血（红细胞数量较少），由于白细胞异常而无法正常抵抗感染，因此更容易受到感染，并且由于缺乏帮助血液凝固的血小板，可能更容易出血。研究这种疾病的科学家认为，这种疾病始于一个异常细胞，该细胞分裂并取代所有其他细胞，也就是说，所有异常细胞都是一个克隆的一部分。在两种类似的疾病中，真性红细胞增多症（骨髓产生过多的红细胞）和原发性血小板增多症（骨髓产生过多的血小板），以及在一些 MF 患者中，科学家发现了似乎引发这些疾病的基因变化。然而，也有一些 MF 患者未发现异常基因。这里的科学家想要研究其他基因，看看是否能找到任何可能引发 MF 的变化。他们解码了 45 名 MF 患者的三个已知与血细胞发育有关的基因的 DNA 序列。他们研究了白细胞和正常颊细胞的 DNA 进行比较。他们发现，45 名患者中有 4 名的骨髓（而非脸颊）的 DNA 携带血小板生成素受体（也称为 MPL）基因突变。该基因对于使血小板正常生长的细胞是必需的。该突变在 MF 相关疾病患者的任何样本中均不存在，在 270 个正常样本中也不存在。鉴定出的突变位于 MPL 基因序列的第 515 位，因此命名为 MPLW515L——W 和 L 是准确指示发生了哪种变化的简写方式。这一变化意味着该基因变得异常活跃。研究人员通过将异常基因放入实验室培养的细胞中来测试其效果。他们发现它使细胞比正常情况生长得更快。此外，当将带有异常基因的细胞放入小鼠体内时，小鼠会出现与患有 MF 的人类相似的血液疾病。 这里发现的基因变化似乎是某些患者出现 MF 的原因。已知 MPL 基因是控制某些血细胞发育的基因途径的一部分。然而，目前尚不清楚这里发现的基因变化究竟如何导致血细胞异常生长，或者如何导致 MF 的其他临床影响。还需要做进一步的工作，看看是否有可能开发出可以作用于这种基因突变或其影响的其他基因的药物，从而使细胞恢复正常。 请通过此摘要的在线版本访问这些网站：http://dx.doi.org/10.1371/journal.pmed.0030270。 • MedlinePlus，美国国家健康图书馆的网站，提供有关骨髓纤维化和相关疾病的信息页 • 资助多种癌症研究的国家癌症研究所提供有关骨髓纤维化患者的信息，包括临床试验信息 • MPD 基金会提供有关骨髓纤维化和相关疾病患者的信息 通过突变 - MPLW515L- 激活 JAK-STAT 信号传导 血小板生成素受体似乎在某些骨髓纤维化患者的发病机制中发挥作用。
The JAK2V617F allele has recently been identified in patients with polycythemia vera (PV), essential thrombocytosis (ET), and myelofibrosis with myeloid metaplasia (MF). Subsequent analysis has shown that constitutive activation of the JAK-STAT signal transduction pathway is an important pathogenetic event in these patients, and that enzymatic inhibition of JAK2V617F may be of therapeutic benefit in this context. However, a significant proportion of patients with ET or MF are JAK2V617F-negative. We hypothesized that activation of the JAK-STAT pathway might also occur as a consequence of activating mutations in certain hematopoietic-specific cytokine receptors, including the erythropoietin receptor (EPOR), the thrombopoietin receptor (MPL), or the granulocyte-colony stimulating factor receptor (GCSFR). DNA sequence analysis of the exons encoding the transmembrane and juxtamembrane domains of EPOR, MPL, and GCSFR, and comparison with germline DNA derived from buccal swabs, identified a somatic activating mutation in the transmembrane domain of MPL (W515L) in 9% (4/45) of JAKV617F-negative MF. Expression of MPLW515L in 32D, UT7, or Ba/F3 cells conferred cytokine-independent growth and thrombopoietin hypersensitivity, and resulted in constitutive phosphorylation of JAK2, STAT3, STAT5, AKT, and ERK. Furthermore, a small molecule JAK kinase inhibitor inhibited MPLW515L-mediated proliferation and JAK-STAT signaling in vitro. In a murine bone marrow transplant assay, expression of MPLW515L, but not wild-type MPL, resulted in a fully penetrant myeloproliferative disorder characterized by marked thrombocytosis (Plt count 1.9–4.0 × 10 12/L), marked splenomegaly due to extramedullary hematopoiesis, and increased reticulin fibrosis. Activation of JAK-STAT signaling via MPLW515L is an important pathogenetic event in patients with JAK2V617F-negative MF. The bone marrow transplant model of MPLW515L-mediated myeloproliferative disorders (MPD) exhibits certain features of human MF, including extramedullary hematopoiesis, splenomegaly, and megakaryocytic proliferation. Further analysis of positive and negative regulators of the JAK-STAT pathway is warranted in JAK2V617F-negative MPD. Myelofibrosis with myeloid metaplasia (MF) is one of a group of chronic blood disorders, known as chronic myeloproliferative disorders. These disorders sometimes turn into acute leukemia. The main abnormality in myelofibrosis is for the bone marrow to become filled with fibrous (scar) tissue (hence the name myelofibrosis), which stops it from producing normal blood cells efficiently. In addition, the white blood cells that remain are abnormal (that is, metaplastic). The clinical effect of these abnormalities are that patients are anemic (they have low numbers of red cells), are more likely to get infections because of the abnormal white cells which cannot fight infections normally, and may bleed more easily because of a lack of the platelets that help the blood to clot. Scientists who study this disorder believe that the disease starts from just one abnormal cell, which divides to replace all the other cells—that is, all the abnormal cells are part of one clone. In two similar diseases, polycythemia vera (in which the bone marrow produces too many red blood cells) and essential thrombocytosis (in which the bone marrow produces too many platelets), and in some patients with MF, scientists have found genetic changes which seem to trigger these diseases. However, there are some patients with MF in which no abnormal gene has been found. The scientists here wanted to look at other genes to see if they could find any changes that might trigger MF. They decoded the DNA sequence of three genes that are known to be involved in how blood cells develop for 45 patients with MF. They looked at DNA from white blood cells, and also from normal cheek cells for comparison. They found that in four of the 45 patients the DNA in the bone marrow, but not the cheek, carried a mutation in a gene for the thrombopoietin receptor (also called MPL). This gene is necessary for the cells that make platelets to grow correctly. The mutation was not present in any samples from patients with diseases related to MF, nor in 270 normal samples. The mutation that was identified was at position 515 in the MPL gene sequence, hence the name MPLW515L—the W and the L are the shorthand way of indicating exactly which change occurred. The change meant that the gene became abnormally active. The researchers tested the effect of the abnormal gene by putting it into cells grown in culture in the laboratory; they found that it made the cells grow more than was normal. In addition, when cells with the abnormal gene were put into mice, the mice developed a blood disorder similar to that seen in humans with MF. It seems likely that the genetic change that has been identified here is responsible for the MF that develops in some patients. The MPL gene is known to be part of a pathway of genes that control how certain blood cells develop. However, it is not yet clear exactly how the genetic change found here causes the blood cells to grow abnormally, or how it causes the other clinical effects of MF. Further work will also need to be done to see if it is possible to develop drugs that can act on this gene mutation, or on the other genes that it affects so as to return the cells to normal. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030270. • MedlinePlus, a Web site of the US National Library of Health, has pages of information on myelofibrosis and related diseases • The National Cancer Institute, which funds research into many cancers, has information for patients on myelofibrosis, including information on clinical trials • The MPD Foundation has information for patients with myelofibrosis and related diseases Activation of JAK-STAT signaling via a mutation - MPLW515L- in the thrombopoietin receptor seems to have a role in the pathogenesis of some patients with myelofibrosis.
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影响因子：
64.8
作者：
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通讯作者：
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50.3
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20.3
作者：
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通讯作者：
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