Prima V, Gore L, Caires A, Boomer T, Yoshinari M, Imaizumi M, Varella-Garcia M, Hunger S P
Department of Pediatrics, University of Florida College of Medicine and the University of Florida Shands Cancer Center, Gainesville, FL 32610, USA.
Leukemia. 2005 May;19(5):806-13. doi: 10.1038/sj.leu.2403684.
We analyzed the TS-2 acute lymphoblastic leukemia (ALL) cell line that contains a t(1;19)(q23;p13.3) but lacks E2A-PBX1 fusion typically present in leukemias with this translocation. We found that the t(1;19) in TS-2 fuses the 19p13 gene DAZAP1 (Deleted in Azoospermia-Associated Protein 1) to the 1q23 gene MEF2D (Myocyte Enhancer Factor 2D), leading to expression of reciprocal in-frame DAZAP1/MEF2D and MEF2D/DAZAP1 transcripts. MEF2D is a member of the MEF2 family of DNA binding proteins that activate transcription of genes involved in control of muscle cell differentiation, and signaling pathways that mediate response to mitogenic signals and survival of neurons and T-lymphocytes. DAZAP1 is a novel RNA binding protein expressed most abundantly in the testis. We demonstrate that MEF2D/DAZAP1 binds avidly and specifically to DNA in a manner indistinguishable from that of native MEF2D and is a substantially more potent transcriptional activator than MEF2D. We also show that DAZAP1/MEF2D is a sequence-specific RNA-binding protein. MEF2D has been identified as a candidate oncogene in murine retroviral insertional mutagenesis studies. Our data implicate MEF2D in human cancer and suggest that MEF2D/DAZAP1 and/or DAZAP1/MEF2D contribute to leukemogenesis by altering signaling pathways normally regulated by wild-type MEF2D and DAZAP1.
我们分析了TS - 2急性淋巴细胞白血病（ALL）细胞系，该细胞系含有t(1;19)(q23;p13.3)，但缺乏通常在具有这种易位的白血病中出现的E2A - PBX1融合基因。我们发现TS - 2中的t(1;19)将19p13基因DAZAP1（无精症相关蛋白1缺失）与1q23基因MEF2D（肌细胞增强因子2D）融合，导致产生相互的读框内DAZAP1/MEF2D和MEF2D/DAZAP1转录本。MEF2D是DNA结合蛋白MEF2家族的成员，可激活参与肌肉细胞分化控制的基因转录，以及介导对有丝分裂信号反应和神经元及T淋巴细胞存活的信号通路。DAZAP1是一种新型RNA结合蛋白，在睾丸中表达最为丰富。我们证明MEF2D/DAZAP1以与天然MEF2D难以区分的方式 avidly且特异性地结合DNA，并且是比MEF2D更强效的转录激活剂。我们还表明DAZAP1/MEF2D是一种序列特异性RNA结合蛋白。在小鼠逆转录病毒插入诱变研究中，MEF2D已被鉴定为候选癌基因。我们的数据表明MEF2D与人类癌症有关，并提示MEF2D/DAZAP1和/或DAZAP1/MEF2D通过改变通常由野生型MEF2D和DAZAP1调节的信号通路而促成白血病发生。
