Aberrant expression of SALL4 in acute B cell lymphoblastic leukemia: mechanism, function, and implication for a potential novel therapeutic target.
Aberrant expression of SALL4 in acute B cell lymphoblastic leukemia: mechanism, function, and implication for a potential novel therapeutic target.
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DOI：
10.1016/j.exphem.2014.01.005
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发表时间：
2014-04
影响因子：
2.6
通讯作者：
Chai, Li
中科院分区：
文献类型：
--
作者：
Ueno, Shikiko;Lu, Jiayun;He, Jie;Li, Ailing;Zhang, XiaoXian;Ritz, Jerome;Silberstein, Leslie E.;Chai, Li
高危儿童和成人急性B细胞淋巴母细胞白血病（B-ALL）的治疗仍然具有挑战性。探索B-ALL的新途径可能会导致新的治疗方法。我们先前的研究表明，干细胞因子SALL 4在B-ALL中异常表达，但其功能作用和解释其在B-ALL中上调的机制尚未探索。为了解决这个问题，我们首先调查了现有的B-ALL细胞系和原代患者样本的SALL 4表达。然后，我们选择具有最高SALL 4表达的B-ALL细胞系进行功能研究。RNA干扰用于下调这些细胞系中的SALL 4表达。当与对照细胞相比时，SALL 4敲低细胞在体外表现出降低的细胞增殖、增加的细胞凋亡，并且在体内异种移植模型中表现出降低的植入。基因表达分析显示，在SALL 4敲低的B-ALL细胞中，参与细胞凋亡途径的多个caspase成员上调。接下来，我们探讨了B-ALL中SALL 4异常表达的机制。我们发现SALL 4 CpG岛的低甲基化与其高表达相关。此外，用DNA甲基化抑制剂处理低SALL 4表达的B-ALL细胞系导致SALL 4 CpG的去甲基化和SALL 4表达增加。总之，据我们所知，我们是第一个表明SALL 4在B-ALL中的异常表达与低甲基化相关，并且SALL 4在B-ALL细胞存活中起关键作用，并且可能是B-ALL治疗中的潜在新靶点。
Treatment for high-risk pediatric and adult acute B cell lymphoblastic leukemia (B-ALL) remains challenging. Exploring novel pathways in B-ALL could lead to new therapy. Our previous study has shown that stem cell factor SALL4 is aberrantly expressed in B-ALL, but its functional roles and the mechanism that accounts for its upregulation in B-ALL remain unexplored. To address this question, we first surveyed the existing B-ALL cell lines and primary patient samples for SALL4 expression. We then selected the B-ALL cell lines with the highest SALL4 expression for functional studies. RNA interference was used to downregulate SALL4 expression in these cell lines. When compared with control cells, SALL4 knockdown cells exhibited decreased cell proliferation, increased apoptosis in vitro, and decreased engraftment in a xenotransplant model in vivo. Gene expression analysis showed that in SALL4 knockdown B-ALL cells, multiple caspase members involved in cell apoptosis pathway were upregulated. Next, we explored the mechanisms of aberrant SALL4 expression in B-ALL. We found that hypomethylation of the SALL4 CpG islands was correlated with its high expression. Furthermore, treatment of low SALL4-expressing B-ALL cell lines with DNA methylation inhibitor led to demethylation of the SALL4 CpG and increased SALL4 expression. In summary, to our knowledge, we are the first to show that the aberrant expression of SALL4 in B-ALL is associated with hypomethylation, and that SALL4 plays a key role in B-ALL cell survival and could be a potential novel target in B-ALL treatment.
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影响因子：
51.1
作者：
Den Boer, Monique L.;van Slegtenhorst, Marjon;De Menezes, Renee X.;Cheok, Meyling H.;Buijs-Gladdines, Jessica G. C. A. M.;Peters, Susan T. C. J. M.;Van Zutven, Laura C. M.;Beverloo, H. Berna;Van der Spek, Peter J.;Escherich, Gaby;Horstmann, Martin A.;Janka-Schoub, Gritta E.;Kamps, Willem A.;Evans, William E.;Pieters, Rob
通讯作者：
Pieters, Rob
影响因子：
2.8
作者：
Deisch, Jeremy;Raisanen, Jack;Rakheja, Dinesh
通讯作者：
Rakheja, Dinesh
影响因子：
6.4
作者：
Habano, Wataru;Sugai, Tamotsu;Nakamura, Shin-Ichi
通讯作者：
Nakamura, Shin-Ichi
影响因子：
5.6
作者：
Wang, Fenghua;Liu, Aijun;Cao, Dengfeng
通讯作者：
Cao, Dengfeng
影响因子：
20.3
作者：
Harvey, Richard C.;Mullighan, Charles G.;Willman, Cheryl L.
通讯作者：
Willman, Cheryl L.