Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Campus M. de Unamuno s/n, 37007 Salamanca, Spain.
Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain.
Int J Mol Sci. 2018 May 17;19(5):1494. doi: 10.3390/ijms19051494.
Due to the clonal nature of human leukemia evolution, all leukemic cells carry the same leukemia-initiating genetic lesions, independently of the intrinsic tumoral cellular heterogeneity. However, the latest findings have shown that the mode of action of oncogenes is not homogeneous throughout the developmental history of leukemia. Studies on different types of hematopoietic tumors have shown that the contribution of oncogenes to leukemia is mainly mediated through the epigenetic reprogramming of the leukemia-initiating target cell. This driving of cancer by a malignant epigenetic stem cell rewiring is, however, not exclusive of the hematopoietic system, but rather represents a common tumoral mechanism that is also at work in epithelial tumors. Tumoral epigenetic reprogramming is therefore a new type of interaction between genes and their target cells, in which the action of the oncogene modifies the epigenome to prime leukemia development by establishing a new pathological tumoral cellular identity. This reprogramming may remain latent until it is triggered by either endogenous or environmental stimuli. This new view on the making of leukemia not only reveals a novel function for oncogenes, but also provides evidence for a previously unconsidered model of leukemogenesis, in which the programming of the leukemia cellular identity has already occurred at the level of stem cells, therefore showing a role for oncogenes in the timing of leukemia initiation.
由于人类白血病进化的克隆性质，所有白血病细胞都携带相同的白血病起始遗传病变，而与内在肿瘤细胞异质性无关。然而，最新的发现表明，癌基因的作用模式在白血病的整个发展历史中并不均匀。对不同类型造血肿瘤的研究表明，癌基因对白血病的贡献主要是通过白血病起始靶细胞的表观遗传重编程来介导的。这种由恶性表观遗传干细胞重布线驱动的癌症并不仅限于造血系统，而是一种常见的肿瘤机制，也存在于上皮肿瘤中。因此，肿瘤表观遗传重编程是基因与其靶细胞之间的一种新型相互作用，其中癌基因的作用通过建立新的病理性肿瘤细胞身份来改变表观基因组，从而为白血病的发展做好准备。这种重编程可能保持潜伏状态，直到受到内源性或环境刺激的触发。这种关于白血病发生的新观点不仅揭示了癌基因的新功能，而且为以前未被考虑的白血病发生模型提供了证据，其中白血病细胞身份的编程已经在干细胞水平上发生，因此表明癌基因在白血病起始时间上发挥作用。
