Lyu Boris N, Ismailov Sanzhar B, Ismailov Bolat, Lyu Marina B
Scientific Center for Anti-Infectious Drugs, Almaty, Kazakhstan.
Theor Biol Med Model. 2008 Nov 11;5:23. doi: 10.1186/1742-4682-5-23.
The high sensitivity of hematopoietic cells, especially stem cells, to radiation and to pro-oxidative and other leukemogenic agents is related to certain of their morphological and metabolic features. It is attributable to the low (minimal) number of active mitochondria and the consequently slow utilization of O2 entering the cell. This results in an increased intracellular partial pressure of O2 (pO2) and increased levels of reactive oxygen (ROS) and nitrogen (RNS) species, and a Delta(PO - AO) imbalance between the pro-oxidative (PO) and antioxidative (AO) constituents.
Because excessive O2 is toxic, we suggest that hematopoietic cells exist in a kind of unstable dynamic balance. This suggestion is based on the idea that mitochondria not only consume O2 in the process of ATP production but also constitute the main anti-oxygenic stage in the cell's protective antioxidative system. Variations in the mitochondrial base capacity (quantity and quality of mitochondria) constitute an important and highly efficient channel for regulating the oxidative stress level within a cell.The primary target for leukemogenic agents is the few mitochondria within the hematopoietic stem cell. Disturbance and weakening of their respiratory function further enhances the initial pro-oxidative state of the cell. This readily results in peroxygenation stress, creating the necessary condition for inducing leukemogenesis. We propose that this is the main cause of all related genetic and other disorders in the cell. ROS, RNS and peroxides act as signal molecules affecting redox-sensitive transcription factors, enzymes, oncogenes and other effectors. Thereby, they influence the expression and suppression of many genes, as well as the course and direction of proliferation, differentiation, leukemogenesis and apoptosis.Differentiation of leukemic cells is blocked at the precursor stage. While the transformation of non-hematopoietic cells into tumor cells starts during proliferation, hematopoietic cells become leukemic at one of the interim stages in differentiation, and differentiation does not continue beyond that point. Proliferation is switched to differentiation and back according to a trigger principle, again involving ROS and RNS. When the leukemogenic DeltaL(PO - AO) imbalance decreases in an under-differentiated leukemia cell to the differentiation level DeltaD(PO - AO), the cell may continue to differentiate to the terminal stage.
The argument described in this article is used to explain the causes of congenital and children's leukemia, and the induction of leukemia by certain agents (vitamin K3, benzene, etc.). Specific research is required to validate the proposals made in this article. This will require accurate and accessible methods for measuring and assessing oxidative stress in different types of cells in general, and in hematopoietic cells in particular, in their different functional states.
造血细胞，尤其是干细胞，对辐射、促氧化及其他致白血病因子具有高度敏感性，这与其某些形态学和代谢特征有关。这归因于活性线粒体数量少（最少），以及因此导致进入细胞的氧气利用缓慢。这会导致细胞内氧分压（pO2）升高，活性氧（ROS）和活性氮（RNS）水平增加，以及促氧化（PO）和抗氧化（AO）成分之间的Δ(PO - AO)失衡。
由于过量的氧气具有毒性，我们认为造血细胞处于一种不稳定的动态平衡中。这一观点基于线粒体不仅在ATP生成过程中消耗氧气，而且还构成细胞保护性抗氧化系统中的主要抗氧阶段这一理念。线粒体基础能力（线粒体的数量和质量）的变化构成了调节细胞内氧化应激水平的重要且高效的途径。致白血病因子的主要靶标是造血干细胞内数量稀少的线粒体。其呼吸功能的紊乱和减弱进一步增强了细胞最初的促氧化状态。这很容易导致过氧化应激，为诱导白血病发生创造了必要条件。我们认为这是细胞内所有相关遗传和其他紊乱的主要原因。ROS、RNS和过氧化物作为信号分子影响氧化还原敏感的转录因子、酶、癌基因和其他效应器。从而，它们影响许多基因的表达和抑制，以及增殖、分化、白血病发生和凋亡的进程与方向。白血病细胞的分化在前体阶段受阻。非造血细胞向肿瘤细胞的转化在增殖过程中开始，而造血细胞在分化的中间阶段之一变成白血病细胞，并且分化不会超过这一点继续进行。增殖根据触发原则转换为分化，然后再转换回增殖，这同样涉及ROS和RNS。当未分化白血病细胞中致白血病的ΔL(PO - AO)失衡降至分化水平ΔD(PO - AO)时，细胞可能会继续分化至终末阶段。
本文所述观点用于解释先天性和儿童白血病的病因，以及某些因子（维生素K₃、苯等）诱发白血病的原因。需要进行具体研究来验证本文提出的观点。这将需要准确且可及的方法来测量和评估一般不同类型细胞，特别是造血细胞在其不同功能状态下的氧化应激。
