Pabst T, Mueller B U
Institute of Medical Oncology, University Hospital, Bern, Switzerland.
Oncogene. 2007 Oct 15;26(47):6829-37. doi: 10.1038/sj.onc.1210765.
The current paradigm on leukemogenesis indicates that leukemias are propagated by leukemic stem cells. The genomic events and pathways involved in the transformation of hematopoietic precursors into leukemic stem cells are increasingly understood. This concept is based on genomic mutations or functional dysregulation of transcription factors in malignant cells of patients with acute myeloid leukemia (AML). Loss of the CCAAT/enhancer binding protein-alpha (CEBPA) function in myeloid cells in vitro and in vivo leads to a differentiation block, similar to that observed in blasts from AML patients. CEBPA alterations in specific subgroups of AML comprise genomic mutations leading to dominant-negative mutant proteins, transcriptional suppression by leukemic fusion proteins, translational inhibition by activated RNA-binding proteins, and functional inhibition by phosphorylation or increased proteasomal-dependent degradation. The PU.1 gene can be mutated or its expression or function can be blocked by leukemogenic fusion proteins in AML. Point mutations in the RUNX1/AML1 gene are also observed in specific subtypes of AML, in addition to RUNX1 being the most frequent target for chromosomal translocation in AML. These data are persuasive evidence that impaired function of particular transcription factors contributes directly to the development of human AML, and restoring their function represents a promising target for novel therapeutic strategies in AML.
当前白血病发生的范式表明，白血病由白血病干细胞增殖而来。造血前体细胞转化为白血病干细胞所涉及的基因组事件和途径越来越为人所知。这一概念基于急性髓系白血病（AML）患者恶性细胞中的基因组突变或转录因子的功能失调。CCAAT/增强子结合蛋白α（CEBPA）在体外和体内髓系细胞中的功能丧失会导致分化阻滞，类似于在AML患者的原始细胞中观察到的情况。AML特定亚组中的CEBPA改变包括导致显性负性突变蛋白的基因组突变、白血病融合蛋白的转录抑制、活化RNA结合蛋白的翻译抑制以及磷酸化或蛋白酶体依赖性降解增加导致的功能抑制。PU.1基因在AML中可能发生突变，或者其表达或功能可能被白血病融合蛋白阻断。除了RUNX1是AML中最常见的染色体易位靶点外，在AML的特定亚型中也观察到RUNX1/AML1基因的点突变。这些数据有力地证明，特定转录因子功能受损直接导致人类AML的发生，恢复其功能是AML新型治疗策略的一个有前景的靶点。
