NOVEL FUSION PROTEIN IN CMML

描述（申请人的描述）： 鉴定为患者中t（5;12）易位的蛋白产物 慢性粒单核细胞白血病（CMML） 蛋白质将氨基 具有PDGFBR的跨膜和胞质结构域的TEL部分。 TEL是转录因子ETS家族的一员， 被描述为多种形式的重排的共同位点， 白血病 PDGFBR的情况尚未如此。 申请人发现， 然而，在初步结果中，另一名CMML患者 新的t（5;7）易位。 Southern印迹分析表明， 在该患者中，在PDGFBR中的相同基因组定位处存在断裂点， t（5;12）易位。 他们的假设是，在这个病人中， 对于t（5;12）TEL-PDGFR患者，PDGFBR被以下物质组成性激活 与7 q24伴侣融合。 虽然罕见（如TEL的识别）， 7 q24处的PDGFBR融合配偶体可以鉴定参与更广泛的 恶性肿瘤组。 此外，鉴于其他患者 CMML具有含PDGFR的融合，7 q24区域经常被 在MDS中缺失的，克隆，表征和操作这个 融合蛋白至关重要。 因此，在具体目标1中，他们将使用 锚定PCR以克隆断裂点。 它们特定的寡核苷酸来自 已知的PDGFBR序列 在具体目标2中，他们将获得一个完整的 长度cDNA，并通过进行核糖核酸酶 保护测定和映射回7号染色体。 最后，对于具体的 目的3他们建议通过测定其 使用突变和 生化分析

DESCRIPTION (Applicant's Description): The TEL-PDGFBR fusion protein was identified as the protein product of a t(5;12) translocation in a patient with chronic myelomonocytic leukemia (CMML). The protein fuses the amino portion of TEL with the transmembrane and cytoplasmic domains of the PDGFBR. TEL, a member of the ETS family of transcription factors, has subsequently been described as a common site of rearrangement in multiple forms of leukemia. This is not yet the case for the PDGFBR. The applicants find, however, in the Preliminary Results, that another patient with CMML has a novel t(5;7) translocation. Southern blotting analysis has identified a breakpoint in this patient at the same genomic localization in the PDGFBR as the t(5;12) translocation. Their hypothesis is, that in this patient, as for the t(5;12) TEL-PDGFR patients, PDGFBR is constitutively activated by fusion with a 7q24 partner. Although rare (as for identification of TEL), the PDGFBR fusion partner at 7q24 may identify a gene involved in a broader group of malignancies. Also, in light of the facts that other patients with CMML have PDGFR containing fusions and the region of 7q24 is frequently deleted in MDS, the cloning, characterization and manipulation of this fusion protein is paramount. Hence, in Specific Aim 1, they will use anchored PCR to clone the breakpoint. Their specific oligos will come from the known PDGFBR sequence. In Specific Aim 2, they will obtain a full length cDNA and determine the relevance of this by performing ribonuclease protection assays and mapping back to chromosome 7. Finally, for Specific Aim 3 they propose to characterize the fusion protein by determining its transforming, activity(s) and biological properties using mutational and biochemical analyses.