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靶向 SLFN11 调控的通路可恢复急性髓系白血病对化疗的敏感性。

Targeting SLFN11-regulated pathways restores chemotherapy sensitivity in AML.

作者信息

Small Sara H, Perez Ricardo E, Beauchamp Elspeth M, Baran Aneta H, Willis Stephen D, Fischietti Mariafausta, Schieber Michael, Kocherginsky Masha, Saleiro Diana, Platanias Leonidas C

机构信息

Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL.

Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL.

出版信息

Blood Neoplasia. 2024 Aug 28;1(4):100037. doi: 10.1016/j.bneo.2024.100037. eCollection 2024 Dec.

DOI:10.1016/j.bneo.2024.100037
PMID:40552140
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12182837/
Abstract

Chemoresistance represents an ongoing challenge in treating patients with acute myeloid leukemia (AML), and a better understanding of the resistance mechanisms can lead to the development of novel AML therapies. Here, we demonstrated that low expression of the DNA damage response gene Schlafen 11 () correlates with poor overall survival and worse prognosis in patients with AML. Moreover, we showed that SLFN11 plays an essential role in regulating chemotherapy sensitivity in AML. AML cells with suppressed levels of SLFN11 do not undergo apoptosis in response to cytarabine because of aberrant activation of the Ataxia telangiectasia and Rad3-related protein (ATR)/Checkpoint kinase 1 (Chk1) pathway, allowing for DNA damage repair, whereas sensitivity to cytarabine can be restored by inhibiting the ATR pathway. Importantly, knockout AML cells retain sensitivity to hypomethylating agents and the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax. Altogether, these results reveal as an important regulator and predictor of chemotherapy sensitivity in AML and suggest that targeting pathways suppressed by SLFN11 may offer potential combination therapies to enhance and optimize chemotherapy responses in AML.

摘要

化疗耐药是治疗急性髓系白血病（AML）患者时面临的一个持续挑战，更好地了解耐药机制有助于开发新的AML治疗方法。在此，我们证明DNA损伤反应基因Schlafen 11（SLFN11）的低表达与AML患者的总生存期较差和预后不良相关。此外，我们表明SLFN11在调节AML化疗敏感性中起关键作用。SLFN11水平受抑制的AML细胞因共济失调毛细血管扩张症和Rad3相关蛋白（ATR）/检查点激酶1（Chk1）通路的异常激活而对阿糖胞苷不发生凋亡，从而允许DNA损伤修复，而通过抑制ATR通路可恢复对阿糖胞苷的敏感性。重要的是，SLFN11基因敲除的AML细胞对低甲基化药物和B细胞淋巴瘤2（BCL-2）抑制剂维奈克拉仍保持敏感性。总之，这些结果揭示SLFN11是AML化疗敏感性的重要调节因子和预测指标，并表明靶向被SLFN11抑制的通路可能提供潜在的联合治疗方法，以增强和优化AML的化疗反应。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/59cd/12182837/05b6f2f91765/BNEO_NEO-2024-000191-gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/59cd/12182837/fc33b7838077/BNEO_NEO-2024-000191-ga1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/59cd/12182837/85aaa3ca0513/BNEO_NEO-2024-000191-gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/59cd/12182837/d44c85586e22/BNEO_NEO-2024-000191-gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/59cd/12182837/cd19275371eb/BNEO_NEO-2024-000191-gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/59cd/12182837/fd8fc81fb7b1/BNEO_NEO-2024-000191-gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/59cd/12182837/cf1c23daa9ae/BNEO_NEO-2024-000191-gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/59cd/12182837/05b6f2f91765/BNEO_NEO-2024-000191-gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/59cd/12182837/fc33b7838077/BNEO_NEO-2024-000191-ga1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/59cd/12182837/85aaa3ca0513/BNEO_NEO-2024-000191-gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/59cd/12182837/d44c85586e22/BNEO_NEO-2024-000191-gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/59cd/12182837/cd19275371eb/BNEO_NEO-2024-000191-gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/59cd/12182837/fd8fc81fb7b1/BNEO_NEO-2024-000191-gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/59cd/12182837/cf1c23daa9ae/BNEO_NEO-2024-000191-gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/59cd/12182837/05b6f2f91765/BNEO_NEO-2024-000191-gr6.jpg

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