Yokoyama Akihiko
National Cancer Center Tsuruoka Metabolomics Laboratory.
Rinsho Ketsueki. 2021;62(8):988-997. doi: 10.11406/rinketsu.62.988.
Leukemia is caused by uncontrolled proliferation of immature hematopoietic progenitors. MLL fusion proteins, generated by chromosomal translocations, activate a broad range of previously transcribed genes to achieve the same expression profile as that of the parent cell in the daughter cells, thereby promoting self-renewal. Normally, replication of the expression profile only occurs in the hematopoietic stem cells (HSCs). A transactivation system comprised of MLL and AF4/ENL/P-TEFb (AEP) complexes promotes it by reactivating CpG-rich promoters. In the normal hematopoietic development, this system is tightly regulated and progressively suppressed during the course of hematopoietic differentiation so that non-HSC hematopoietic cells would not self-renew. Genetic mutations such as fusions of MLL and AEP components generate a constitutively active form of the MLL transcriptional machinery, which aberrantly promotes self-renewal even in non-HSC hematopoietic cells. In this review, I depict a molecular mechanism of MLL fusion-mediated leukemogenesis from a standpoint that leukemogenesis is driven by aberrant self-renewal that is mediated by hyper-active transcriptional machinery, and introduce several molecularly targeted therapies in the making which specifically perturb this transactivation system.
白血病是由未成熟造血祖细胞的不受控制的增殖引起的。由染色体易位产生的MLL融合蛋白激活广泛的先前转录的基因，以在子细胞中实现与亲代细胞相同的表达谱，从而促进自我更新。正常情况下，表达谱的复制仅发生在造血干细胞（HSC）中。由MLL和AF4/ENL/P-TEFb（AEP）复合物组成的反式激活系统通过重新激活富含CpG的启动子来促进这一过程。在正常的造血发育过程中，该系统受到严格调控，并在造血分化过程中逐渐受到抑制，以使非HSC造血细胞不会自我更新。诸如MLL和AEP组分融合之类的基因突变产生MLL转录机制的组成型活性形式，其即使在非HSC造血细胞中也异常地促进自我更新。在这篇综述中，我从白血病发生是由过度活跃的转录机制介导的异常自我更新驱动的角度描述了MLL融合介导的白血病发生的分子机制，并介绍了几种正在研发的特异性干扰这种反式激活系统的分子靶向疗法。
