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Targeting SLFN11-regulated pathways restores chemotherapy sensitivity in AML
Sara H Small1,2,3,4, Ricardo E Perez1, Elspeth M Beauchamp1,2,5
1Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL.
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.
Insights
Low expression of Schlafen 11 (SLFN11) predicts poor outcomes in acute myeloid leukemia (AML). Restoring SLFN11 function or inhibiting the ATR pathway may overcome chemoresistance in AML patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Chemoresistance is a major obstacle in treating acute myeloid leukemia (AML).
- Understanding resistance mechanisms is crucial for developing effective AML therapies.
Purpose of the Study:
- To investigate the role of Schlafen 11 (SLFN11) in AML chemoresistance.
- To identify SLFN11 as a potential therapeutic target for AML.
Main Methods:
- Correlating SLFN11 expression with patient survival and prognosis.
- Assessing the impact of SLFN11 levels on AML cell apoptosis and chemotherapy sensitivity.
- Investigating the role of the ATR/Chk1 pathway in SLFN11-mediated chemoresistance.
- Evaluating the sensitivity of SLFN11 knockout AML cells to different therapeutic agents.
Main Results:
- Low SLFN11 expression is linked to poor survival and prognosis in AML patients.
- SLFN11 regulates chemotherapy sensitivity; its suppression leads to cytarabine resistance via ATR/Chk1 activation.
- Inhibiting the ATR pathway restores cytarabine sensitivity in AML cells with low SLFN11.
- SLFN11 knockout AML cells remain sensitive to hypomethylating agents and venetoclax.
Conclusions:
- SLFN11 is a key regulator and predictor of chemotherapy sensitivity in AML.
- Targeting pathways suppressed by SLFN11 may offer novel combination therapies to improve AML treatment outcomes.
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