TP53-mutated acute myeloid leukemia (AML) remains highly resistant to current therapies. In this study, we used genome-wide CRISPR/Cas9 screens, along with transcriptomic and proteomic analyses, to identify the XPO7–NPAT pathway as a critical vulnerability in TP53-mutant AML. While XPO7 acts as a tumor suppressor in TP53-wild-type AML by sustaining nuclear p53, it paradoxically promotes proliferation in TP53-mutant AML by retaining NPAT in the nucleus. NPAT loss leads to global histone depletion and replication stress. Analysis of human AML datasets and patient-derived xenografts confirms the oncogenic role of this pathway. Our findings, now published in Blood, offer new insights and therapeutic opportunities for this hard-to-treat leukemia subtype. Congrats Yuichiro!