Smoljo Tomislav, Tomic Barbara, Lalic Hrvoje, Dembitz Vilma, Batinic Josip, Bedalov Antonio, Visnjic Dora
Laboratory for Cell Biology, Department of Physiology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia.
Division of Hematology, Department of Internal Medicine, University Hospital Centre Zagreb, Zagreb, Croatia.
Front Pharmacol. 2023 Oct 26;14:1258151. doi: 10.3389/fphar.2023.1258151. eCollection 2023.
Low-dose cytarabine (LDAC) is a standard therapy for elderly acute myeloid leukemia (AML) patients unfit for intensive chemotherapy. While high doses of cytarabine induce cytotoxicity, the precise mechanism of action of LDAC in AML remains elusive. studies have demonstrated LDAC-induced differentiation; however, such differentiation is seldom observed . We hypothesize that this discrepancy may be attributed to the influence of bone marrow (BM) stromal cells on AML cells. Thus, this study aimed to investigate the impact of BM stromal cells on LDAC-induced differentiation of AML cell lines and primary samples. Our results demonstrate that the presence of MS-5 stromal cells prevented LDAC-induced cell cycle arrest, DNA damage signaling and differentiation of U937 and MOLM-13 cell lines. Although transcriptomic analysis revealed that the stroma reduces the expression of genes involved in cytokine signaling and oxidative stress, data obtained with pharmacological inhibitors and neutralizing antibodies did not support the role for CXCL12, TGF-β1 or reactive oxygen species. The presence of stromal cells reduces LDAC-induced differentiation in primary samples from AML-M4 and myelodysplastic syndrome/AML patients. In conclusion, our study demonstrates that BM stroma reduces differentiation of AML induced by LDAC. These findings provide insights into the limited occurrence of terminal differentiation observed in AML patients, and suggest a potential explanation for this observation.
小剂量阿糖胞苷（LDAC）是不适于强化化疗的老年急性髓系白血病（AML）患者的标准治疗方法。虽然高剂量阿糖胞苷可诱导细胞毒性，但LDAC在AML中的精确作用机制仍不清楚。研究已证实LDAC可诱导分化；然而，这种分化很少被观察到。我们推测这种差异可能归因于骨髓（BM）基质细胞对AML细胞的影响。因此，本研究旨在探讨BM基质细胞对LDAC诱导的AML细胞系和原代样本分化的影响。我们的结果表明，MS-5基质细胞的存在可阻止LDAC诱导的U937和MOLM-13细胞系的细胞周期停滞、DNA损伤信号传导和分化。虽然转录组分析显示基质可降低参与细胞因子信号传导和氧化应激的基因表达，但用药物抑制剂和中和抗体获得的数据并不支持CXCL12、TGF-β1或活性氧的作用。基质细胞的存在可降低AML-M4和骨髓增生异常综合征/AML患者原代样本中LDAC诱导的分化。总之，我们的研究表明BM基质可降低LDAC诱导的AML分化。这些发现为AML患者中观察到的终末分化发生率有限提供了见解，并为这一观察结果提出了潜在的解释。
