Cancer therapy-induced long-term bone marrow injury

描述（由申请人提供）：许多接受化疗和/或电离辐射（IR）的患者发生急性和残留（或长期）骨髓（BM）损伤，这限制了癌症治疗的成功并对其生活质量产生不利影响。急性骨髓抑制是在快速增殖的造血祖细胞（HPC）中诱导凋亡的结果，并且在相对静止的造血干细胞（HSC）中诱导凋亡的程度较低。其临床表现已成功地管理使用各种造血生长因子。相反，残余BM损伤在很大程度上归因于HSC衰老的诱导。然而，化疗和/或IR诱导HSC衰老的分子机制尚未明确，也没有开发出有效的治疗方法来改善残留的BM损伤。我们实验室和其他人最近的研究为HSC损伤提供了新的见解。首先，我们发现小鼠暴露于亚致死剂量的全身照射（TBI）仅在HSC中扰乱还原/氧化（氧化还原）反应的平衡，导致活性氧（ROS）产生的持续和延长的增加。第二，HSC比HPC和其他造血细胞对ROS诱导的氧化损伤更敏感。此外，ROS损伤HSC似乎不是通过先前假设的非特异性细胞毒性作用。相反，损伤至少部分是通过p38促分裂原活化蛋白激酶（p38）-p16 lnk 4a（p16）途径的氧化还原依赖性激活诱导细胞衰老介导的。基于这些新的发现，我们推测化疗和IR通过ROS介导的p38-p16通路的激活选择性诱导HSC衰老，从而导致残留的BM损伤。因此，我们预测抗氧化剂可用于有效减轻残余BM损伤。此外，抗氧化治疗通过抑制化疗和IR诱导的遗传不稳定性为癌症患者提供了额外的益处，遗传不稳定性是继发性肿瘤的主要原因，也是肿瘤耐药性发展的促成因素。因此，这种策略提供了显着改善生活质量和提高癌症患者化疗和放疗的疗效的承诺。

DESCRIPTION (provided by applicant): Many patients receiving chemotherapy and/or ionizing radiation (IR) develop acute and residual (or long- term) bone marrow (BM) injury that limits the success of cancer treatment and adversely affects their quality of life. Acute myelosuppression is the result of the induction of apoptosis in the rapidly proliferating hematopoietic progenitor cells (HPCs) and to a lesser degree in the relatively quiescent hematopoietic stem cells (HSCs). Its clinical manifestations have been successfully managed by the use of various hematopoietic growth factors. In contrast, residual BM injury has been largely attributed to the induction of HSC senescence. However, neither the molecular mechanisms by which chemotherapy and/or IR induce HSC senescence have been clearly defined, nor has an effective treatment been developed to ameliorate residual BM injury. Recent studies from our laboratory and others provide new insights into HSC damage. First, we have found that exposure of mice to a sublethal dose of total body irradiation (TBI) perturbs the balance of reduction/oxidation (redox) reactions ONLY in HSCs, leading to a persistent and prolonged increase in reactive oxygen species (ROS) production. Second, HSCs are more sensitive to ROS-induced oxidative damage than HPCs and other hematopoietic cells. Moreover, it appears that ROS injures HSCs not by a nonspecific cytotoxic effect as previously hypothesized. Instead, the damage is at least partially mediated by induction of cellular senescence through redox-dependent activation of the p38 mitogen-activated protein kinase (p38)-p16lnk4a (p16) pathway. Based on these novel findings, we hypothesize that chemotherapy and IR cause residual BM injury by SELECTIVELY inducing HSC senescence through ROS-mediated activation of the p38-p16 pathway. Thus, we predict that antioxidants can be used to effectively mitigate residual BM injury. Moreover, antioxidant therapy provides additional benefits to cancer patients by suppressing chemotherapy- and IR-induced genetic instability, a primary cause of secondary tumors and a contributing factor to the development of tumor resistance. Therefore, this strategy offers the promise of significantly improving the quality of life and increasing the efficacy of chemotherapy and radiotherapy for cancer patients.