A majority of infant and pediatric leukemias are caused by the mixed‐lineage leukemia gene (MLL ) fused with a variety of candidates. Several underlying mechanisms have been proposed. One currently popular view is that truncated MLL1 fusion and its associated complex constitutively hijacks super elongation complex, including positive transcription elongation factor b, CDK9, and cyclin T1 complex and DOT1L, to enhance the expression of transcription factors that maintain or restore stemness of leukocytes, as well as prevent the differentiation of hematopoietic progenitor cells. An alternative emerging view proposes that MLL1‐fusion promotes the recruitment of TATA binding protein and RNA polymerase II (Pol II) initiation complex, so as to increase the expression levels of target genes. The fundamental mechanism of both theories are gain of function for truncated MLL1 fusions, either through Pol II elongation or initiation. Our recent progress in transcription regulation of paused Pol II through JMJD5, JMJD6, and JMJD7, combined with the repressive role of H3K4me3 revealed by others, prompted us to introduce a contrarian hypothesis: the failure to shut down transcribing units by MLL‐fusions triggers the transformation: loss of function of truncated MLL1 fusions coupled with the loss of conversion of H3K4me1 to H3K4me3, leading to the constitutive expression of transcription factors that are in charge of maintenance of hematopoietic progenitor cells, may trigger the transformation of normal cells into cancer cells. Following this track, a potential treatment to eliminate these fusion proteins, which may ultimately cure the disease, is proposed.

中文翻译：

---

MLL融合引起的白血病潜在的潜在机制和可能的治疗方法。

大多数婴儿和小儿白血病是由混合谱系白血病基因（MLL）与各种候选人融合在一起。已经提出了几种潜在的机制。目前一种流行的观点是，截短的MLL1融合及其相关复合物组成性劫持了超延伸复合物，包括正转录延伸因子b，CDK9和cyclin T1复合物以及DOT1L，以增强维持或恢复白细胞干性的转录因子的表达，以及防止造血祖细胞的分化。另一种新兴观点认为，MLL1融合促进TATA结合蛋白和RNA聚合酶II（Pol II）起始复合物的募集，从而增加靶基因的表达水平。两种理论的基本机理都是通过Pol II延伸或启动来获得截短的MLL1融合的功能。我们最近通过JMJD5，JMJD6和JMJD7在暂停的Pol II转录调控中取得的进展，以及其他人揭示的H3K4me3的抑制作用，促使我们引入了一个逆势假设：MLL融合无法关闭转录单位会触发转化：截短的MLL1融合蛋白的功能丧失以及H3K4me1到H3K4me3的转化损失，导致负责维持造血祖细胞的转录因子的组成型表达，可能触发正常细胞向癌细胞的转化。遵循这一思路，提出了一种消除这些融合蛋白的潜在治疗方法，最终可以治愈该疾病。结合其他人揭示的H3K4me3的抑制作用，促使我们引入了逆势假设：MLL融合无法关闭转录单位会触发转化：截短的MLL1融合功能丧失，以及H3K4me1转化为H3K4me1 H3K4me3导致负责维持造血祖细胞的转录因子的组成型表达，可能会触发正常细胞向癌细胞的转化。遵循这一思路，提出了一种消除这些融合蛋白的潜在治疗方法，最终可以治愈该疾病。结合其他人揭示的H3K4me3的抑制作用，促使我们引入了逆势假设：MLL融合无法关闭转录单位会触发转化：截短的MLL1融合功能丧失，以及H3K4me1转化为H3K4me1 H3K4me3导致负责维持造血祖细胞的转录因子的组成型表达，可能会触发正常细胞向癌细胞的转化。遵循这一思路，提出了一种消除这些融合蛋白的潜在治疗方法，最终可以治愈该疾病。截短的MLL1融合蛋白功能丧失，以及H3K4me1到H3K4me3转化的丧失，导致负责维持造血祖细胞的转录因子的组成型表达，可能会触发正常细胞向癌细胞的转化。遵循这一思路，提出了一种消除这些融合蛋白的潜在治疗方法，最终可以治愈该疾病。截短的MLL1融合蛋白功能丧失，以及H3K4me1到H3K4me3转化的丧失，导致负责维持造血祖细胞的转录因子的组成型表达，可能会触发正常细胞向癌细胞的转化。遵循这一思路，提出了一种消除这些融合蛋白的潜在治疗方法，最终可以治愈该疾病。