Targeting SLFN11-regulated pathways restores chemotherapy sensitivity in AML

Blood Neoplasia Pub Date : 2024-08-28 DOI:10.1016/j.bneo.2024.100037

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

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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 (SLFN11) 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, SLFN11 knockout AML cells retain sensitivity to hypomethylating agents and the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax. Altogether, these results reveal SLFN11 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.

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靶向 SLFN11 调控通路可恢复急性髓细胞白血病化疗敏感性

摘要抗化疗是治疗急性髓性白血病（AML）患者的一个持续挑战，更好地了解抗化疗机制有助于开发新的AML疗法。在这里，我们证明了DNA损伤应答基因Schlafen 11（SLFN11）的低表达与急性髓性白血病患者的总生存率低和预后差相关。此外，我们还发现，SLFN11 在调节 AML 化疗敏感性方面起着至关重要的作用。由于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，SLFN11 水平受抑制的 AML 细胞不会对阿糖胞苷产生凋亡反应，从而进行 DNA 损伤修复，而对阿糖胞苷的敏感性可通过抑制 ATR 通路得到恢复。重要的是，SLFN11基因敲除的急性髓细胞保持了对低甲基化药物和B细胞淋巴瘤2（BCL-2）抑制剂venetoclax的敏感性。总之，这些结果揭示了 SLFN11 是急性髓细胞性白血病化疗敏感性的重要调节因子和预测因子，并表明针对 SLFN11 抑制的通路可能提供潜在的联合疗法，以增强和优化急性髓细胞性白血病的化疗反应。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Blood Neoplasia

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