Six1 regulates leukemia stem cell maintenance in acute myeloid leukemia
Six1 regulates leukemia stem cell maintenance in acute myeloid leukemia
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Six1 调节急性髓性白血病中白血病干细胞的维持
DOI：
10.1111/cas.14033
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发表时间：
2019-07-01
期刊：
影响因子：
5.7
通讯作者：
Yuan, Weiping
中科院分区：
文献类型：
--
作者：
Chu, Yajing;Chen, Yangpeng;Yuan, Weiping
急性髓性白血病（AML）的分子遗传学改变在白血病发生中起着至关重要的作用，包括复发性染色体易位、表观遗传/剪接体突变和转录因子畸变。Six 1是Sine oculis homeobox（Six）家族的一个转录因子，已被证明与Eya合作将正常造血祖细胞转化为白血病。然而，Six 1在白血病维持中的具体作用和潜在机制尚未探索。在这里，我们发现AML患者和小鼠白血病干细胞（c-Kit（+）细胞，LSC）中SIX 1的表达增加。重要的是，我们还观察到，人类患者中Six 1水平越高，预后越差。值得注意的是，Six 1的敲低显著延长了MLL-AF 9诱导的AML小鼠的存活，同时降低了外周浸润和肿瘤负荷。通过免疫表型、集落形成能力和有限稀释试验评估，来自Six 1基因敲低（KD）小鼠的AML细胞显示LSC数量和功能显著降低。进一步分析显示Six 1 KD小鼠LSC凋亡增加，糖酵解基因表达减少。总的来说，我们的数据表明Six 1通过维持LSC池对MLL-AF 9诱导的AML的进展至关重要。
Molecular genetic changes in acute myeloid leukemia (AML) play crucial roles in leukemogenesis, including recurrent chromosome translocations, epigenetic/spliceosome mutations and transcription factor aberrations. Six1, a transcription factor of the Sine oculis homeobox (Six) family, has been shown to transform normal hematopoietic progenitors into leukemia in cooperation with Eya. However, the specific role and the underlying mechanism of Six1 in leukemia maintenance remain unexplored. Here, we showed increased expression of SIX1 in AML patients and murine leukemia stem cells (c-Kit(+) cells, LSCs). Importantly, we also observed that a higher level of Six1 in human patients predicts a worse prognosis. Notably, knockdown of Six1 significantly prolonged the survival of MLL-AF9-induced AML mice with reduced peripheral infiltration and tumor burden. AML cells from Six1-knockdown (KD) mice displayed a significantly decreased number and function of LSC, as assessed by the immunophenotype, colony-forming ability and limiting dilution assay. Further analysis revealed the augmented apoptosis of LSC and decreased expression of glycolytic genes in Six1 KD mice. Overall, our data showed that Six1 is essential for the progression of MLL-AF9-induced AML via maintaining the pool of LSC.