Mixed-lineage-leukemia (MLL) fusion protein collaborates with Ras to induce acute leukemia through aberrant Hox expression and Raf activation
Mixed-lineage-leukemia (MLL) fusion protein collaborates with Ras to induce acute leukemia through aberrant Hox expression and Raf activation
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DOI：
10.1038/leu.2009.177
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发表时间：
2009-12-01
期刊：
影响因子：
11.4
通讯作者：
Nosaka, T.
中科院分区：
文献类型：
--
作者：
Ono, R.;Kumagai, H.;Nosaka, T.
混合系白血病(MLL)融合癌基因与婴幼儿急性白血病密切相关，常伴有FMS样受体酪氨酸激酶3(Flt3)突变或过表达。早期的研究表明，MLL融合蛋白在小鼠模型中与另一种突变(如Flt3突变)一起诱导急性白血病。然而，到目前为止，关于白血病发生中协同作用的分子机制还很少被阐明。本研究利用MLL融合介导的小鼠白血病发生的体外致癌模型和体内急性白血病模型系统，研究了协同白血病发生中的分子网络。本研究表明，MLL融合蛋白在体内协同激活RAS，在体外可替代RAF，但不协同信号转导和转录激活子5(STAT5)的激活，在体内诱导急性白血病和体外致癌转化。此外，MLL靶向的关键分子之一Hoxa9和体内RAS的激活(在体外可被Raf取代)被鉴定为足以模拟MLL融合介导的白血病发生的基本成分。这些发现提示，HOX分子的异常表达(S)和激活的Raf之间的分子串扰可能在MLL融合介导的白血病发生中起关键作用，从而可能有助于开发新型的分子靶向治疗MLL相关白血病。白血病(2009年)232197-2209；doi：10.1038/leu 2009.177；在线发布
Mixed-lineage-leukemia (MLL) fusion oncogenes are closely involved in infant acute leukemia, which is frequently accompanied by mutations or overexpression of FMS-like receptor tyrosine kinase 3 (FLT3). Earlier studies have shown that MLL fusion proteins induced acute leukemia together with another mutation, such as an FLT3 mutant, in mouse models. However, little has hitherto been elucidated regarding the molecular mechanism of the cooperativity in leukemogenesis. Using murine model systems of the MLL-fusion-mediated leukemogenesis leading to oncogenic transformation in vitro and acute leukemia in vivo, this study characterized the molecular network in the cooperative leukemogenesis. This research revealed that MLL fusion proteins cooperated with activation of Ras in vivo, which was substitutable for Raf in vitro, synergistically, but not with activation of signal transducer and activator of transcription 5 (STAT5), to induce acute leukemia in vivo as well as oncogenic transformation in vitro. Furthermore, Hoxa9, one of the MLL-targeted critical molecules, and activation of Ras in vivo, which was replaceable with Raf in vitro, were identified as fundamental components sufficient for mimicking MLL-fusion-mediated leukemogenesis. These findings suggest that the molecular crosstalk between aberrant expression of Hox molecule(s) and activated Raf may have a key role in the MLL-fusion-mediated-leukemogenesis, and may thus help develop the novel molecularly targeted therapy against MLL-related leukemia. Leukemia (2009) 23, 2197-2209; doi:10.1038/leu.2009.177; published online 27 August 2009