Molecular drug targets in myeloproliferative neoplasms: mutant ABL1, JAK2, MPL, KIT, PDGFRA, PDGFRB and FGFR1.
Molecular drug targets in myeloproliferative neoplasms: mutant ABL1, JAK2, MPL, KIT, PDGFRA, PDGFRB and FGFR1.
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DOI：
10.1111/j.1582-4934.2008.00559.x
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发表时间：
2009-02
影响因子：
5.3
通讯作者：
Tefferi A
中科院分区：
文献类型：
--
作者：
Tefferi A
骨髓增生性肿瘤(MPN)的癌蛋白包括bcr-abl1和重排的PDGFR蛋白。后者是染色体内(如FIP1L1-PDGFRA)或染色体间(如ETV6-PDGFRb)基因融合的产物。BCR-ABL1与慢性粒细胞白血病(CML)和突变型PDGFR相关，其MPN表型以嗜酸性粒细胞增多为特征，此外，在FIP1L1-PDGFRA的情况下，骨髓肥大细胞增多。这些基因-表型相关性已被有效地用于开发高精度的诊断分析和分子靶向治疗。希望在具有特定基因改变的其他MPN中也发生同样的情况：真性红细胞增多症(JAK2V617F和其他JAK2突变)、原发性血小板增多症(JAK2V617F和MPL515突变)、原发性骨髓纤维化(JAK2V617F和MPL515突变)、全身性肥大细胞增多症(KITD816V和其他KIT突变)和干细胞白血病/淋巴瘤(ZNF198-FGFR1和其他FGFR1融合基因)。目前的综述讨论了上述突变分子作为药物靶点的价值。
Therapeutically validated oncoproteins in myeloproliferative neoplasms (MPN) include BCR-ABL1 and rearranged PDGFR proteins. The latter are products of intra- (e.g. FIP1L1-PDGFRA) or inter-chromosomal (e.g.ETV6-PDGFRB) gene fusions. BCR-ABL1 is associated with chronic myelogenous leukaemia (CML) and mutant PDGFR with an MPN phenotype characterized by eosinophilia and in addition, in case of FIP1L1-PDGFRA, bone marrow mastocytosis. These genotype-phenotype associations have been effectively exploited in the development of highly accurate diagnostic assays and molecular targeted therapy. It is hoped that the same will happen in other MPN with specific genetic alterations: polycythemia vera (JAK2V617F and other JAK2 mutations), essential thrombocythemia (JAK2V617F and MPL515 mutations), primary myelofibrosis (JAK2V617F and MPL515 mutations), systemic mastocytosis (KITD816V and other KIT mutations) and stem cell leukaemia/lymphoma (ZNF198-FGFR1 and other FGFR1 fusion genes). The current review discusses the above-listed mutant molecules in the context of their value as drug targets.
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