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Acute myeloid leukemia (AML) with TP53 mutations is almost universally refractory to chemotherapy, molecular-targeted therapies, and hematopoietic stem cell transplantation, leading to dismal clinical outcomes. The lack of effective treatments underscores the urgent need for novel therapeutic strategies. Using genome-wide CRISPR/Cas9 dropout screens in isogenic Trp53-wild-type (WT) and Trp53-knockout mouse AML models, combined with transcriptomic and proteomic analyses of AML samples from mice and humans, we identify the XPO7-NPAT (exportin 7-nuclear protein, coactivator of histone transcription) pathway as essential for TP53-mutated AML cell survival. In TP53-WT AML, XPO7 functions as a tumor suppressor by regulating the nuclear abundance of p53 protein, particularly when basal levels of functional p53 are high. However, in TP53-mutated AML, XPO7 drives leukemia proliferation by retaining NPAT, an XPO7-associated protein predominantly expressed in TP53-mutated AML, within the nucleus. NPAT depletion induces genome-wide histone loss, compromises genomic integrity, and triggers replication catastrophe in TP53-mutated AML cells. Notably, the analysis of publicly available AML data sets, primary AML samples, and single-cell intrapatient mRNA profiles further reveals elevated XPO7 and NPAT expression in TP53-mutated AML. Finally, we validate the XPO7-NPAT pathway as a critical driver of leukemia progression in vivo using patient-derived xenograft models of TP53-WT and TP53-mutant AML. Our study delineates key molecular mechanisms underlying TP53-mutated AML pathogenesis and identifies the XPO7-NPAT axis as a critical vulnerability in this refractory leukemia subtype.