Panagopoulos I, Fioretos T, Isaksson M, Samuelsson U, Billström R, Strömbeck B, Mitelman F, Johansson B
Department of Clinical Genetics, University Hospital, SE-221 85 Lund, Sweden.
Hum Mol Genet. 2001 Feb 15;10(4):395-404. doi: 10.1093/hmg/10.4.395.
The CBP gene at 16p13 fuses to MOZ and MLL as a result of the t(8;16)(p11;p13) in acute (myelo)monocytic leukemias (AML M4/M5) and the t(11;16)(q23;p13) in treatment-related AML, respectively. We show here that a novel t(10;16)(q22;p13) in a childhood AML M5a leads to a MORF-CBP chimera. RT-PCR using MORF forward and CBP reverse primers amplified a MORF-CBP fusion in which nucleotide 3103 of MORF was fused in-frame with nucleotide 284 of CBP. Nested RT-PCR with CBP forward and MORF reverse primers generated a CBP-MORF transcript in which nucleotide 283 of CBP was fused in-frame with nucleotide 3104 of MORF. Genomic analyses revealed that the breaks were close to Alu elements in intron 16 of MORF and intron 2 of CBP and that duplications had occurred near the breakpoints. A database search using MORF cDNA enabled us to construct an exon-intron map of the MORF gene. The MORF-CBP protein retains the zinc fingers, two nuclear localization signals, the histone acetyltransferase (HAT) domain, a portion of the acidic domain of MORF and the CBP protein downstream of codon 29. Thus, the part of CBP encoding the RARA-binding domain, the CREB-binding domain, the three Cys/His-rich regions, the bromodomain, the HAT domain and the Glu-rich domains is present. In the reciprocal CBP-MORF, part of the acidic domain and the C-terminal Ser- and Met-rich regions of MORF are likely to be driven by the CBP promoter. Since both fusion transcripts were present, their exact role in the leukemogenic process remains to be elucidated.
在急性（髓）单核细胞白血病（AML M4/M5）中，16p13上的CBP基因因t(8;16)(p11;p13)而与MOZ融合，在治疗相关的AML中，因t(11;16)(q23;p13)而与MLL融合。我们在此展示，一名儿童AML M5a中的新型t(10;16)(q22;p13)导致了MORF-CBP嵌合体的产生。使用MORF正向引物和CBP反向引物进行的RT-PCR扩增出一个MORF-CBP融合体，其中MORF的第3103个核苷酸与CBP的第284个核苷酸框内融合。使用CBP正向引物和MORF反向引物进行的巢式RT-PCR产生了一个CBP-MORF转录本，其中CBP的第283个核苷酸与MORF的第3104个核苷酸框内融合。基因组分析显示，断裂点靠近MORF内含子16和CBP内含子2中的Alu元件，并且在断点附近发生了重复。使用MORF cDNA进行的数据库搜索使我们能够构建MORF基因的外显子-内含子图谱。MORF-CBP蛋白保留了锌指、两个核定位信号、组蛋白乙酰转移酶（HAT）结构域、MORF酸性结构域的一部分以及密码子29下游的CBP蛋白。因此，编码RARA结合结构域、CREB结合结构域、三个富含Cys/His的区域、溴结构域、HAT结构域和富含Glu的结构域的CBP部分存在。在反向的CBP-MORF中，MORF酸性结构域的一部分以及C末端富含Ser和Met的区域可能由CBP启动子驱动。由于两种融合转录本都存在，它们在白血病发生过程中的确切作用仍有待阐明。
