Department of Molecular Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, Lodz 90-236, Poland.
Int J Mol Sci. 2013 Aug 7;14(8):16348-64. doi: 10.3390/ijms140816348.
Chronic myeloid leukemia (CML) is a hematological malignancy that arises from the transformation of stem hematopoietic cells by the fusion oncogene BCR/ABL and subsequent clonal expansion of BCR/ABL-positive progenitor leukemic cells. The BCR/ABL protein displays a constitutively increased tyrosine kinase activity that alters many regulatory pathways, leading to uncontrolled growth, impaired differentiation and increased resistance to apoptosis featured by leukemic cells. Current CML therapy is based on tyrosine kinase inhibitors (TKIs), primarily imatinib, which induce apoptosis in leukemic cells. However, some patients show primary resistance to TKIs while others develop it in the course of therapy. In both cases, resistance may be underlined by perturbations in apoptotic signaling in leukemic cells. As mitochondria may play an important role in such signaling, alteration in mitochondrial metabolism may change resistance to pro-apoptotic action of TKIs in BCR/ABL-positive cells. Because BCR/ABL may induce reactive oxygen species and unfaithful DNA repair, it may affect the stability of mitochondrial DNA, influencing mitochondrial apoptotic signaling and in this way change the sensitivity of CML cells to TKIs. Moreover, cancer cells, including BCR/ABL-positive cells, show an increased level of glucose metabolism, resulting from the shift from oxidative phosphorylation to glycolysis to supply ATP for extensive proliferation. Enhanced level of glycolysis may be associated with TKI resistance and requires change in the expression of several genes regulated mostly by hypoxia-inducible factor-1α, HIF-1α. Such regulation may be associated with the impaired mitochondrial respiratory system in CML cells. In summary, mitochondria and mitochondria-associated molecules and pathways may be attractive targets to overcome TKI resistance in CML.
慢性髓细胞白血病（CML）是一种血液系统恶性肿瘤，由融合癌基因 BCR/ABL 转化造血干细胞，并随后克隆扩增 BCR/ABL 阳性祖细胞白血病细胞引起。BCR/ABL 蛋白显示出组成性增加的酪氨酸激酶活性，改变了许多调节途径，导致白血病细胞不受控制的生长、分化受损和对凋亡的抵抗力增加。目前的 CML 治疗基于酪氨酸激酶抑制剂（TKI），主要是伊马替尼，它诱导白血病细胞凋亡。然而，一些患者对 TKI 表现出原发性耐药，而另一些患者在治疗过程中发展为耐药。在这两种情况下，耐药性可能是由于白血病细胞凋亡信号的改变。由于线粒体可能在这种信号中发挥重要作用，线粒体代谢的改变可能会改变 BCR/ABL 阳性细胞对促凋亡 TKI 作用的耐药性。由于 BCR/ABL 可能诱导活性氧和不忠实的 DNA 修复，它可能会影响线粒体 DNA 的稳定性，影响线粒体凋亡信号，并以这种方式改变 CML 细胞对 TKI 的敏感性。此外，包括 BCR/ABL 阳性细胞在内的癌细胞表现出高水平的葡萄糖代谢，这是由于从氧化磷酸化向糖酵解转变，以供应大量增殖所需的 ATP 所致。增强的糖酵解水平可能与 TKI 耐药性相关，并需要调节大多数由缺氧诱导因子-1α（HIF-1α）调节的几个基因的表达发生变化。这种调节可能与 CML 细胞中线粒体呼吸系统受损有关。总之，线粒体及其相关分子和途径可能是克服 CML 中 TKI 耐药性的有吸引力的靶点。
