TAL1/SCL induces leukemia by inhibiting the transcriptional activity of E47/HEB
TAL1/SCL induces leukemia by inhibiting the transcriptional activity of E47/HEB
复制标题
DOI：
10.1016/j.ccr.2004.05.023
复制
发表时间：
2004-06-01
期刊：
影响因子：
50.3
通讯作者：
Kelliher, M
中科院分区：
文献类型：
--
作者：
O'Neil, J;Shank, J;Kelliher, M
碱性螺旋环螺旋（bHLH）基因TAL 1（或SCL）的激活是T细胞急性淋巴细胞白血病（T-ALL）中常见的功能获得性突变。为了提供tal 1/scl通过干扰E47和HEB诱导白血病的遗传学证据，我们在E2 A或HEB杂合背景中表达了tal 1/scl。由于E47/HEB靶基因的抑制，这些小鼠表现出疾病加速和胸腺细胞发育紊乱。在tal 1/scl胸腺细胞中，我们发现辅阻遏蛋白mSin 3A与CD 4增强子结合，而在野生型胸腺细胞中检测到E47/HEB/p300复合物。此外，tal 1/scl肿瘤对HDAC的药理学抑制敏感并经历细胞凋亡。这些数据表明，tall/scl通过抑制E47/HEB诱导白血病，并表明HDAC抑制剂可证明在表达TAL 1/SCL的T-ALL患者中有效。
Activation of the basic-helix-loop-helix (bHLH) gene TAL1 (or SCL) is a frequent gain-of-function mutation in T cell acute lymphoblastic leukemia (T-ALL). To provide genetic evidence that tal1/scl induces leukemia by interfering with E47 and HEB, we expressed tal1/scl in an E2A or HEB heterozygous background. These mice exhibit disease acceleration and perturbed thymocyte development due to repression of E47/HEB target genes. In tal1/scl thymocytes, we find the corepressor mSin3A bound to the CD4 enhancer, whereas an E47/HEB/p300 complex is detected in wild-type thymocytes. Furthermore, tal1/scl tumors are sensitive to pharmacologic inhibition of HDAC and undergo apoptosis. These data demonstrate that tall/scl induces leukemia by repressing E47/HEB and suggest that HDAC inhibitors may prove efficacious in T-ALL patients who express TAL1/SCL.