SETD2 is the only methyltransferase for H3K36me3, and our previous study has firstly demonstrated that it functioned as one tumor suppressor in hematopoiesis. Consistent with it, SETD2 mutation, which led to its loss of function, was identified in AML. However, the distribution and function of SETD2 mutation in AML remained largely unknown. Herein, we integrated SETD2-mutated AML cases from our center and literature reports, and found that NPM1 mutation was the most common concomitant genetic alteration with SETD2 mutation in AML, with its frequency even higher than MLL rearrangement and AML1-ETO. Though this result indicated the cooperation of SETD2 and NPM1 mutations in leukemogenesis, our functional study showed that SETD2 was required for the proliferation of NPM1-mutated AML cell line OCI-AML3, but not MLL-rearranged AML cell line THP-1, via maintaining its direct target NPM1 expression, which was just opposite to its role of tumor suppressor. Therefore, we speculated that SETD2 possibly had two different faces in distinct subtypes and stages of AML.

中文翻译：

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NPM1突变的急性髓性白血病中的SETD2突变复发

SETD2是H3K36me3的唯一甲基转移酶，我们先前的研究首次证明它在造血过程中起着一种抑癌作用。与之一致的是，在AML中发现了SETD2突变，导致其功能丧失。然而，SETD2突变在AML中的分布和功能仍然未知。在这里，我们从我们的中心和文献报道中整合了SETD2突变的AML病例，发现NPM1突变是AML中最常见的伴随SETD2突变的遗传变异，其发生频率甚至高于MLL重排和AML1-ETO。尽管此结果表明SETD2和NPM1突变在白血病发生中具有协同作用，但我们的功能研究表明，SETD2是NPM1突变的AML细胞系OCI-AML3增殖所必需的，而MLL重排的AML细胞THP-1则不是，通过维持其直接靶向NPM1的表达来实现，这与其抑癌作用相反。因此，我们推测SETD2在AML的不同亚型和阶段中可能具有两个不同的面孔。