Targeting SLFN11-Regulated Pathways Restores Chemotherapy Sensitivity in AML

• AML with high SLFN11 expression is more sensitive to cytarabine and has a better prognosis, suggesting that it may be a new biomarker for AML

• SLFN11 prevents over-activation of the ATR pathway promoting apoptosis in response to cytarabine

Chemoresistance represents an ongoing challenge in treating patients with acute myeloid leukemia (AML) and a better understanding of resistance mechanisms can lead to the development of novel AML therapies. Here we demonstrate that low expression of the DNA damage response gene Schlafen 11 (SLFN11) correlates with poor overall survival and worse prognosis in AML patients. Moreover, we show 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 due to aberrant activation of the ATR/Chk1 pathway allowing for DNA damage repair, while sensitivity to cytarabine can be restored by inhibiting the ATR pathway. Importantly, SLFN11 knockout AML cells retain sensitivity to hypomethylating agents and the 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.