The chronic myeloproliferative disorders and mutation of JAK2: Dameshek's 54 year old speculation comes of age
The chronic myeloproliferative disorders and mutation of JAK2: Dameshek's 54 year old speculation comes of age
复制标题
DOI：
10.1016/j.beha.2006.11.005
复制
发表时间：
2007-03-01
影响因子：
2.1
通讯作者：
Kaushansky, Kenneth
中科院分区：
文献类型：
--
作者：
Kaushansky, Kenneth
1951年，William Dameshek推测了慢性骨髓增生性疾病的共同起源-真性红细胞增多症（PV）、原发性血小板增多症（ET）、慢性特发性骨髓纤维化（IMF）和慢性髓细胞性白血病（CML）。随后的工作表明，所有这些都来自造血干细胞。大约20年前，导致CML的癌基因bcr-abl被发现，最近又发现了导致嗜酸性粒细胞增多综合征和全身性肥大细胞疾病的突变基因。然而，直到最近，PV、ET和IMF的起源仍无法从分子水平上解释。2005年，四个独立的酪氨酸激酶信号转导研究小组报告了Janus激酶（JAK）2细胞质酪氨酸激酶JH 2结构域617位的功能获得性突变，即缬氨酸突变为苯丙氨酸。该突变需要促红细胞生成素、促血小板生成素或粒细胞集落刺激因子受体的存在来发挥功能，该突变导致功能性活动过度，并似乎是造血生长因子超敏反应的原因，这是这些疾病中最典型的发现。事实上，所有PV患者和相当比例的ET和IMF患者都存在这种突变。突变激酶似乎是一个有用的诊断测试骨髓增生性疾病，并可能有预后价值。未来的研究无疑将集中在开发特异性抑制剂作为治疗药物，以及回答一些问题，仍然关于信号强度，基因型和表型表达的作用，并可能涉及额外的尚未确定的突变在这些疾病。
In 195 1, William Dameshek speculated on the common origin of the chronic myeloproliferative disorders-polycythemia vera (PV), essential thrombocythemia (ET), chronic idiopathic myelofibrosis (IMF:), and chronic myelogenous leukemia (CML). Subsequent work suggested that all arose from the hematopoietic stem cell. About 20 years ago the oncogene responsible for CML, bcr-abl, was identified, and more recently the mutant genes that cause hypereosinophilic syndrome and systemic mast cell disorder have been discovered. However, until very recently, the origin of PV, ET, and IMF: have defied molecular explanation. In 2005, four separate groups working on tyrosine kinase signal transduction reported a gain-of-function, valine-to-phenyalanine, mutation at position 617 in the JH2 domain of the Janus kinase (JAK) 2 cytoplasmic tyrosine kinase. This mutation requires the presence of the erythropoietin, thrombopoietin, or granulocyte-colony stimulating factor receptor/s for function, the mutation leads to functional hyperactivity and appears responsible for hematopoietic growth factor hypersensitivity, the most characteristic finding in these disorders. Virtually all patients with PV and substantial proportions of those with ET and IMF have now been shown to harbor this mutation. The mutant kinase appears to be a useful diagnostic test for myeloproliferative disorders and may have prognostic value. Future research will undoubtedly focus on the development of specific inhibitors as therapeutic agents as well as answering a number of questions that remain regarding the role of signal intensity, genotypic and phenotypic expression and the possible involvement of additional as yet unidentified mutations in these disorders.