Transcription factor BACH2 is transcriptionally regulated by the BCR/ABL oncogene
Transcription factor BACH2 is transcriptionally regulated by the BCR/ABL oncogene
复制标题
转录因子 BACH2 受 BCR/ABL 癌基因转录调节
作者：
S. Vieira;M. Deininger;A. Sorour;P. Sinclair;L. Foroni;J. Goldman;J. Melo
Bcr/abl是一种活性酪氨酸激酶，在慢性粒细胞白血病(CML)和Ph阳性急性淋巴细胞白血病(Ph+ALL)的发病机制中起重要作用。用STI571抑制BV173 CML细胞中的BCR/ABL激酶活性，导致一个10kb的新的mRNA显著过表达，发现它是小鼠Bach2的人类同源基因，一种B细胞特异的转录因子。人BACH2基因全长9,120个碱基，包括一个2,526个碱基的开放阅读框，编码一个带有碱性亮氨酸拉链的蛋白质(BZip)和一个btb/POZ结构域，介导DNA结合和异源二聚作用。在BCR/ABL抑制后，所有测试的10个Ph+淋巴系中Bach2持续上调(2-10倍)。在CML髓系细胞系(n=8)和bcr/abl阴性细胞系(n=6)中，Northern blotting检测不到BACH2，或对STI571无反应，提示BCR/ABL对BACH2的抑制可能与淋巴转化特异性相关。定量逆转录聚合酶链式反应显示慢性粒细胞白血病患者(n=24)的BACH2表达水平显著低于正常人(n=23)(P<；0.0005)。此外，在体外用STI571处理的CD34+细胞在10个CML中有8个显示BACH2持续上调，而在9个正常受试者中没有一个。BACH2在BCR/ABL阳性细胞中的转录调控是通过MEK途径进行的，如它们对U0126特异性抑制剂的反应所示。放射杂交定位和FISH结果显示，BACH2位于6号染色体q15带，该区域常与ALL和非霍奇金淋巴瘤的缺失相关，提示其可能是肿瘤抑制基因。然而，在34个淋巴瘤、10个B细胞ALL或7个反应性淋巴结中，Southern blotting没有观察到重排或信号丢失。BACH2在BCR/ABL阳性细胞中的表达模式表明，该调节因子的转录抑制在CML中受到损害，可能是导致淋巴母细胞危机的原因之一。©2001 Wiley-Liss公司
Expression of BCR/ABL, a constitutively active tyrosine kinase, is a primary event in the pathogenesis of chronic myeloid leukemia (CML) and Ph‐positive acute lymphoblastic leukemia (Ph+ALL). Inhibition of the BCR/ABL kinase activity in the BV173 CML cell line with STI571 resulted in a significant overexpression of a 10‐kb novel mRNA, found to be the human ortholog of the murine Bach2, a B‐cell‐specific transcription factor. The human BACH2 cDNA is >9,120 bp long and includes an open reading frame of 2,526 bp encoding a protein with a basic leucine zipper (bZip) and a BTB/POZ domain, mediating DNA‐binding and heterodimerization. BACH2 was consistently upregulated (2–10‐fold) in all 10 Ph+ lymphoid lines tested following BCR/ABL inhibition. In CML myeloid cell lines (n = 8) and BCR/ABL‐negative lines (n = 6), BACH2 was either undetectable by Northern blotting or did not change in response to STI571, suggesting that BACH2 repression by BCR/ABL may be specifically relevant to lymphoid transformation. Quantitative RT/PCR revealed a significantly lower level of BACH2 expression in leukocytes from patients with CML (n = 24) as compared to normal individuals (n = 23) (P < 0.0005). Moreover, CD34+ cells treated in vitro with STI571 exhibited a consistent upregulation of BACH2 in 8 of 10 CMLs but in none of the 9 normal individuals tested. Transcription regulation of BACH2 in BCR/ABL‐positive cells was exerted via the MEK pathways, as shown by their responses to the U0126‐specific inhibitor. Radiation hybrid mapping and FISH revealed that BACH2 is located on chromosome 6, band q15, a region frequently associated with deletions in ALL and non‐Hodgkin's lymphoma, suggesting its possible role as a tumor suppressor gene. However, no rearrangement or loss of signal was observed by Southern blotting in 34 lymphomas, 10 B‐cell ALLs, or seven reactive lymph nodes. The pattern of BACH2 expression in BCR/ABL‐positive cells suggests that transcriptional repression by this regulator is impaired in CML and may contribute to the emergence of lymphoid blast crisis. © 2001 Wiley‐Liss, Inc.
登录
查看更多内容
PI3K-AKT 通路的激活掩盖了法呢基转移酶抑制剂的促凋亡作用。
影响因子：
11.2
作者：
Du,W;Liu,A;Prendergast,GC
通讯作者：
Prendergast,GC
影响因子：
32.4
作者：
Fang, W;Mueller, DL;Behrens, TW
通讯作者：
Behrens, TW
影响因子：
4.8
作者：
Su, L;David, M
通讯作者：
David, M
影响因子：
56.9
作者：
LUGO, TG;PENDERGAST, AM;WITTE, ON
通讯作者：
WITTE, ON