Jackson Robert C, Radivoyevitch Tomas
Pharmacometrics Ltd, 51 North Road, Whittlesford, Cambridge, CB22 4NZ, UK.
Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio, USA.
AAPS J. 2016 Jul;18(4):914-22. doi: 10.1208/s12248-016-9905-2. Epub 2016 Mar 23.
The t(9;22) translocation that causes chronic myeloid leukemia (CML) drives both transformation and the progression process that eventually results in the disease changing to acute leukemia. Constitutively activated Bcr-Abl signaling in CML creates high levels of reactive oxygen species (ROS) that produce 8-oxo-guanine in DNA; this is mutagenic and causes chronic phase (CP) progression to blast phase (BP). We modeled three types of mutations involved in this progression: mutations that result in myeloid progenitor cells proliferating independently of external growth factors; mutations causing failure of myeloid progenitor cells to differentiate; and mutations that enable these cells to survive independently of attachment to marrow stroma. We further modeled tyrosine kinase inhibitors (TKI) as restoring myeloid cell apoptosis and preventing ROS-driven mutagenesis, and mutations that cause TKI resistance. We suggest that the unusually low rate of resistance to TKI arises because these drugs deplete ROS, which in turn decrease mutation rates.
导致慢性粒细胞白血病（CML）的t(9;22)易位驱动了细胞转化以及最终导致疾病转变为急性白血病的进展过程。CML中组成性激活的Bcr-Abl信号传导产生高水平的活性氧（ROS），ROS会在DNA中产生8-氧代鸟嘌呤；这具有致突变性，并导致慢性期（CP）进展为急变期（BP）。我们对这一进展过程中涉及的三种类型的突变进行了建模：导致髓系祖细胞独立于外部生长因子增殖的突变；导致髓系祖细胞分化失败的突变；以及使这些细胞能够在不依赖附着于骨髓基质的情况下存活的突变。我们进一步将酪氨酸激酶抑制剂（TKI）建模为恢复髓系细胞凋亡并预防ROS驱动的诱变作用，以及导致TKI耐药的突变。我们认为，对TKI的耐药率异常低是因为这些药物消耗了ROS，进而降低了突变率。
