Bone marrow stromal cells reduce low-dose cytarabine-induced differentiation of acute myeloid leukemia.
Bone marrow stromal cells reduce low-dose cytarabine-induced differentiation of acute myeloid leukemia.
复制标题
DOI：
10.3389/fphar.2023.1258151
复制
发表时间：
2023
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
低剂量阿糖胞苷（LDAC）是不适合强化化疗的老年急性髓细胞白血病（AML）患者的标准治疗方法。虽然高剂量的阿糖胞苷诱导细胞毒性，但LDAC在AML中的确切作用机制仍然难以捉摸。体外研究已经证明LDAC诱导的分化;然而，这种分化很少在体内观察到。我们推测这种差异可能是由于骨髓（BM）基质细胞对AML细胞的影响。因此，本研究旨在研究骨髓基质细胞对LDAC诱导的AML细胞系和原代样品分化的影响。我们的研究结果表明，MS-5基质细胞的存在下，阻止LDAC诱导的细胞周期停滞，DNA损伤信号和分化的U937和MOLM-13细胞系。尽管转录组学分析显示基质降低了参与细胞因子信号传导和氧化应激的基因的表达，但使用药理学抑制剂和中和抗体获得的数据不支持CXCL 12、TGF-β1或活性氧的作用。基质细胞的存在减少了来自AML-M4和骨髓增生异常综合征/AML患者的原代样品中LDAC诱导的分化。总之，我们的研究表明，骨髓基质减少由LDAC诱导的AML的分化。这些发现为AML患者中观察到的终末分化的有限发生提供了见解，并为这一观察结果提出了潜在的解释。
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. In vitro studies have demonstrated LDAC-induced differentiation; however, such differentiation is seldom observed in vivo. 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.
登录
查看更多内容
小鼠骨髓中多能间充质干细胞的前瞻性鉴定、分离和系统移植。
DOI：
10.1084/jem.20091046
发表时间：
2009-10-26
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Morikawa S;Mabuchi Y;Kubota Y;Nagai Y;Niibe K;Hiratsu E;Suzuki S;Miyauchi-Hara C;Nagoshi N;Sunabori T;Shimmura S;Miyawaki A;Nakagawa T;Suda T;Okano H;Matsuzaki Y
通讯作者：
Matsuzaki Y
影响因子：
29
作者：
Forte D;García-Fernández M;Sánchez-Aguilera A;Stavropoulou V;Fielding C;Martín-Pérez D;López JA;Costa ASH;Tronci L;Nikitopoulou E;Barber M;Gallipoli P;Marando L;Fernández de Castillejo CL;Tzankov A;Dietmann S;Cavo M;Catani L;Curti A;Vázquez J;Frezza C;Huntly BJ;Schwaller J;Méndez-Ferrer S
通讯作者：
Méndez-Ferrer S
影响因子：
3.8
作者：
Dembitz V;Lalic H;Kodvanj I;Tomic B;Batinic J;Dubravcic K;Batinic D;Bedalov A;Visnjic D
通讯作者：
Visnjic D
影响因子：
--
作者：
Zeng H;Gu H;Chen C;Li M;Xia F;Xie L;Liu X;Zhang F;Tong X;Wang J;Yu Z;Zheng J
通讯作者：
Zheng J
影响因子：
3.7
作者：
Meyer M;Rübsamen D;Slany R;Illmer T;Stabla K;Roth P;Stiewe T;Eilers M;Neubauer A
通讯作者：
Neubauer A