LPXN, a Member of the Paxillin Superfamily, Is Fused to RUNX1 in an Acute Myeloid Leukemia Patient with a t(11;21)(q12;q22) Translocation
LPXN, a Member of the Paxillin Superfamily, Is Fused to RUNX1 in an Acute Myeloid Leukemia Patient with a t(11;21)(q12;q22) Translocation
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DOI：
10.1002/gcc.20704
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发表时间：
2009-12-01
影响因子：
3.7
通讯作者：
Zhang, Jun
中科院分区：
文献类型：
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作者：
Dai, Hai-Ping;Xue, Yong-Quan;Zhang, Jun
RUNX1（以前的AML1）参与血液恶性肿瘤的多次复发性染色体重排。最近，我们在急性髓性白血病（AML）患者中发现了RUNX1和LPXN之间的新融合（11;21）（q12;q22）。该易位产生了4个RUNX1/LPXN和1个LPXN/RUNX1嵌合转录本。两种具有代表性的RUNX1/LPXN融合蛋白RL和RLs都定位于细胞核，可以像野生型RUNX1一样将CBFB蛋白带入细胞核。这两种融合蛋白都抑制RUNX1反激活CSF1R启动子的能力，可能是通过竞争其靶序列。与RL和RLs不同，LPXN/RUNX1融合蛋白LR被发现定位于细胞质中。因此，我们认为它对RUNX1的转录活性影响不大。我们还发现融合蛋白RL、RLs、LR和野生型LPXN可以赋予NIH3T3细胞更快速的生长、在软琼脂中形成菌落的能力以及在BALB/c裸鼠皮下组织形成实体瘤的能力等恶性转化特征。综上所述，我们的数据表明RUNX1/LPXN和LPXN/RUNX1融合蛋白可能在白血病发生中发挥重要作用，并且细胞粘附途径的失调可能在AML中具有重要的病理意义。我们的研究也提示LPXN可能在癌变中起重要作用。(C) 2009 Wiley-Liss, Inc。
RUNX1 (previously AML1) is involved in multiple recurrent chromosomal rearrangements in hematological malignances. Recently, we identified a novel fusion between RUNX1 and LPXN from an acute myeloid leukemia (AML) patient with t(11;21)(q12;q22). This translocation generated four RUNX1/LPXN and one LPXN/RUNX1 chimeric transcripts. Two representative RUNX1/LPXN fusion proteins, RL and RLs, were both found to localize in the nucleus and could bring the CBFB protein into the nucleus like the wild-type RUNX1. Both fusion proteins inhibit the ability of RUNX1 to transactivate the CSF1R promoter, probably through competition for its target sequences. Unlike RL and RLs, the LPXN/RUNX1 fusion protein LR was found to localize in the cytoplasm. Thus, we believe it has little impact on the transcriptional activity of RUNX1. We also found that fusion proteins RL, RLs, LR, and wild-type LPXN could confer NIH3T3 cells with malignant transformation characteristics such as more rapid growth, the ability to form colonies in soft agar, and the ability to form solid tumors in the subcutaneous tissue of the BALB/c nude mice. Taken together, our data indicated that the RUNX1/LPXN and LPXN/RUNX1 fusion proteins may play important roles in leukemogenesis and that deregulation of cell adhesion pathways may be pathogenetically important in AML. Our study also suggests that LPXN may play an important role in carcinogenesis. (C) 2009 Wiley-Liss, Inc.