1] Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany [2] Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Leukemia. 2015 Jun;29(6):1243-52. doi: 10.1038/leu.2015.32. Epub 2015 Feb 12.
Genetic abnormalities are a hallmark of cancer. Hereby, cytogenetic aberrations and small-scale abnormalities, such as single-nucleotide variations and insertion/deletion mutations, have emerged as two alternative modes of genetic diversification. Both mechanisms are at work in acute myeloid leukemia (AML), in which conventional karyotyping and molecular studies demonstrate that gene mutations occur predominantly in cytogenetically normal AML, whereas chromosomal changes are a driving force of development and progression of disease in aberrant karyotype AML. All steps of disease evolution in AML, ranging from the transformation of preleukemic clones into overt leukemia to the expansion and recurrence of malignant clones, are paralleled by clonal evolution at either the gene mutation or chromosome aberration level. Preleukemic conditions, such as Fanconi anemia and Bloom syndrome, demonstrate that the acquisition of chromosomal aberrations can contribute to leukemic transformation. Similar to what has been shown at the mutational level, expansion and recurrence of AML clones goes along with increasing genetic diversification. Hereby, cytogenetically more evolved subclones are at a proliferative advantage and outgrow ancestor clones or have evolved toward a more aggressive behavior with additional newly acquired aberrations as compared with the initial leukemic clone, respectively.
遗传异常是癌症的一个标志。因此，细胞遗传学异常和小规模异常，如单核苷酸变异和插入/缺失突变，已经成为两种替代的遗传多样化模式。这两种机制都在急性髓系白血病（AML）中起作用，其中常规核型分析和分子研究表明，基因突变主要发生在细胞遗传学正常的 AML 中，而染色体变化是异常核型 AML 中疾病发展和进展的驱动力。AML 疾病演变的所有步骤，从白血病前克隆转化为显性白血病到恶性克隆的扩增和复发，都伴随着基因突变或染色体异常水平的克隆进化。白血病前状态，如范可尼贫血和布卢姆综合征，表明染色体异常的获得可能有助于白血病转化。类似于在突变水平上所显示的，AML 克隆的扩增和复发伴随着遗传多样化的增加。在此，细胞遗传学上更进化的亚克隆具有增殖优势，并且与原始白血病克隆相比，它们的生长速度更快，或者通过获得额外的新获得的异常而进化为更具侵袭性的行为，而原始白血病克隆则没有。
