Impera Luciana, Lonoce Angelo, Fanfulla Domenica Antonella, Moreilhon Chimene, Legros Laurence, Raynaud Sophie, Storlazzi Clelia Tiziana
Department of Biology, University of Bari ALDO MORO, Italy.
Cancer Genet. 2011 Sep;204(9):512-5. doi: 10.1016/j.cancergen.2011.08.016.
Philadelphia (Ph)-negative myeloproliferative neoplasms (MPNs) are known to harbor alterations of the tyrosine kinase JAK2 (9p24), resulting in the constitutive autoactivation of the encoded protein. Here, we report an unclassifiable MPN case, BCR/ABL1-negative, showing a three-way t(9;18;22)(p23;p11.3;q11.2) translocation, which generates a 5'BCR/3'JAK2 gene by fusing BCR at intron 1 to JAK2 at intron 14 on the derivative chromosome 22. The fusion gene produced two alternatively spliced 5'BCR/3'JAK2 transcripts, fusing in-frame BCR exon 1 to JAK2 exon 15 and exon 17. This is the first report of the simultaneous occurrence of two BCR/JAK2 fusion transcripts in the same sample and of the longer transcript isoform (BCR exon 1 fused to JAK2 exon 15). Notably, both BCR/JAK2 encoded fusion proteins are predicted to juxtapose the coiled-coil dimerization domain of BCR to the catalytically inactive pseudokinase domain (JH2), entirely or partially deprived of the inhibitory region 1 (IR1). Interestingly, IR1 is involved in the auto-inhibitory interaction with the JAK2 kinase domain (JH1), which may result in deregulation of JAK2 activity.
已知费城（Ph）阴性骨髓增殖性肿瘤（MPN）存在酪氨酸激酶JAK2（9p24）改变，导致编码蛋白的组成型自激活。在此，我们报告1例无法分类的MPN病例，BCR/ABL1阴性，显示出三向t(9;18;22)(p23;p11.3;q11.2)易位，该易位在衍生染色体22上通过将内含子1的BCR与内含子14的JAK2融合产生5'BCR/3'JAK2基因。该融合基因产生了两种选择性剪接的5'BCR/3'JAK2转录本，将框架内的BCR外显子1与JAK2外显子15和外显子17融合。这是首次报道在同一样本中同时出现两种BCR/JAK2融合转录本以及较长的转录本异构体（BCR外显子1与JAK2外显子15融合）。值得注意的是，两种BCR/JAK2编码的融合蛋白预计会将BCR的卷曲螺旋二聚化结构域与催化无活性的假激酶结构域（JH2）并列，该结构域完全或部分缺失抑制区域1（IR1）。有趣的是，IR1参与与JAK2激酶结构域（JH1）的自抑制相互作用，这可能导致JAK2活性失调。
