Tefferi Ayalew
Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA.
J Cell Mol Med. 2009 Feb;13(2):215-37. doi: 10.1111/j.1582-4934.2008.00559.x. Epub 2008 Oct 23.
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 (JAK2 V617F and other JAK2 mutations), essential thrombocythemia (JAK2V617F and MPL515 mutations), primary myelofibrosis (JAK2 V617F 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.
在骨髓增殖性肿瘤（MPN）中经治疗验证的癌蛋白包括BCR-ABL1和重排的血小板衍生生长因子受体（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）相关，而突变型PDGFR与以嗜酸性粒细胞增多为特征的MPN表型相关，此外，在FIP1L1-PDGFRA的情况下，还与骨髓肥大细胞增多症相关。这些基因型-表型关联已在高精度诊断检测和分子靶向治疗的开发中得到有效利用。希望在其他具有特定基因改变的MPN中也会如此：真性红细胞增多症（JAK2 V617F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（JAK2 V617F和MPL515突变）、系统性肥大细胞增多症（KITD816V和其他KIT突变）以及干细胞白血病/淋巴瘤（ZNF198-FGFR1和其他FGFR1融合基因）。本综述在上述突变分子作为药物靶点的价值背景下对其进行了讨论。
