Hassan H T, Zander A
Department of Hematology and Oncology, Hamburg University Hospital Eppendorf, Germany.
Acta Haematol. 1996;95(3-4):257-62. doi: 10.1159/000203893.
Stem cell factor (SCF) is an essential hematopoietic cytokine that interacts with other cytokines to preserve the viability of hematopoietic stem and progenitor cells, to influence their entry into the cell cycle and to facilitate their proliferation and differentiation. SCF on its own cannot drive noncycling hematopoietic progenitor cells into the cell cycle but does prevent their apoptotic death. SCF when combined with other cytokines increases the cloning efficacy of hematopoietic progenitor cells from all lineages. SCF also stimulates the growth of CD34+ leukemic progenitor cells from most patients with acute myeloid leukemia (AML). The mRNA expression of the SCF receptor c-kit has been shown to be significantly increased in all fresh AML blast cells compared with normal controls (healthy volunteers), in particular CD34+ cells. Two inhibitory cytokines, transforming growth factor-beta and interleukin-4, decreased c-kit expression, whereas tumor necrosis factor-alpha increased c-kit expression, but chemotherapeutic drugs showed no effect on c-kit expression, but chemotherapeutic drugs showed no effect on c-kit expression in AML cells. Apoptosis has been shown to be directly related to a high complete remission rate in AML patients following induction therapy. Since SCF has been shown to stimulate the proliferation of mainly CD34+ AML cells, we have investigated whether the poor response of patients with CD34+ myeloid leukemia cells to chemotherapy could be due to SCF-induced resistance to apoptosis. The effect of SCF on the apoptosis induced by chemotherapeutic drugs commonly used in the treatment of AML - cytarabine, daunorubicin and carboplatin - was examined in human CD34+ myeloid leukemia cells in serum-free cultures. SCF significantly reduced the induced apoptosis by more than 50% in all CD34+ human leukemia cells treated by any of the three chemotherapeutic drugs. Antibodies blocking c-kit reversed the significant inhibitory effect of SCF on chemotherapy-induced apoptosis, confirming the role of SCF in the resistance to chemotherapy-induced apoptosis in CD34+ human leukemia. These results suggest that the poor response of patients with CD34+ leukemia cells could be at least partially due to less chemotherapy-induced apoptosis resulting from protection by SCF as an adjuvant mechanism for drug resistance in myeloid leukemia. We conclude that an antisense strategy to block c-kit expression in AML blast cells may prove valuable for decreasing the chemoresistance of AML patients. The abrogation of leukemic resistance to apoptotic death through anti-SCF/c-pit expression combined with chemotherapy offers potential for designing novel therapeutic approaches for refractory AML patients.
干细胞因子（SCF）是一种重要的造血细胞因子，它与其他细胞因子相互作用，以维持造血干细胞和祖细胞的活力，影响它们进入细胞周期，并促进其增殖和分化。单独的SCF不能驱使非周期性造血祖细胞进入细胞周期，但能防止它们发生凋亡性死亡。SCF与其他细胞因子联合使用时，可提高所有谱系造血祖细胞的克隆效率。SCF还能刺激大多数急性髓系白血病（AML）患者的CD34⁺白血病祖细胞的生长。与正常对照（健康志愿者）相比，所有新鲜AML原始细胞，尤其是CD34⁺细胞中，SCF受体c-kit的mRNA表达均显著增加。两种抑制性细胞因子，即转化生长因子-β和白细胞介素-4，可降低c-kit表达，而肿瘤坏死因子-α则增加c-kit表达，但化疗药物对AML细胞中的c-kit表达无影响。凋亡已被证明与AML患者诱导治疗后的高完全缓解率直接相关。由于SCF已被证明主要刺激CD34⁺AML细胞的增殖，我们研究了CD34⁺髓系白血病细胞患者对化疗反应不佳是否可能是由于SCF诱导的凋亡抵抗。在无血清培养的人CD34⁺髓系白血病细胞中，检测了SCF对AML治疗中常用化疗药物——阿糖胞苷、柔红霉素和卡铂诱导凋亡的影响。在所有用这三种化疗药物之一处理的CD34⁺人白血病细胞中，SCF显著降低诱导的凋亡超过50%。阻断c-kit的抗体逆转了SCF对化疗诱导凋亡的显著抑制作用，证实了SCF在CD34⁺人白血病对化疗诱导凋亡的抵抗中的作用。这些结果表明，CD34⁺白血病细胞患者反应不佳可能至少部分是由于SCF作为髓系白血病耐药的辅助机制提供保护，导致化疗诱导的凋亡减少。我们得出结论，在AML原始细胞中阻断c-kit表达的反义策略可能对降低AML患者的化疗耐药性有价值。通过抗SCF/c-kit表达联合化疗消除白血病对凋亡性死亡的抵抗，为设计难治性AML患者的新型治疗方法提供了潜力。
