Background: Cancer chemotherapeutics often lead to significant toxicities. Identifying alternative strategies that do not cause direct cytotoxicity is desirable. Results: Partial ATP depletion induces AML differentiation without direct cytotoxicity in an ATR/Chk1-dependent fashion. Conclusion: Partial ATP depletion is a promising strategy for AML. Significance: Characterizing therapeutic strategies that do not involve direct cytotoxicity is important to improve cancer therapy.