The XPO7-NPAT axis represents key vulnerabilities in TP53-mutated acute myeloid leukemia (scRNA-Seq)

Mutation of TP53, a tumor suppressor in cancer, is common and leads to extremely poor prognosis. To identify vulnerabilities in TP53-mutated tumors, we performed genome-wide CRISPR/Cas9 screens using isogenic Trp53 wild-type and knockout mouse acute myeloid leukemia (AML) lines. Here, we show that histone gene regulation governed by the XPO7-NPAT pathway is essential for survival of TP53-mutated AML cells. In TP53 wild-type cells, XPO7 enhances p53 nuclear localization and functions as a tumor suppressor, but in TP53-mutated cells, XPO7 promotes cell proliferation by retaining NPAT, a histone gene activator, in the nucleus. NPAT depletion led to genome-wide histone loss, enhancing vulnerability to genotoxic stress. Human AML cases show predominant expression of XPO7 and NPAT when TP53 is mutated, suggesting a potential therapeutic vulnerability. Overall design: To assess intra-patient profiles of NPAT/XPO7 mRNA expression and their correlation with TP53 mutational status at single-cell levels, we performed single-cell RNA-seq (scRNA-seq) using BM cells from two TP53-mutated AML cases.