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The prognosis of acute myeloid leukemia (AML) with KMT2A::MLLT3 rearrangement and MECOM overexpression and/or KRAS mutation is dismal, and the optimal treatment strategy remains unclear. However, to the best of our knowledge, a suitable model (such as a cell line or its xenograft model) for research on this subtype has not been established. We established a novel AML cell line, YCU-AML2, and its xenograft model harboring KMT2A::MLLT3 rearrangement, MECOM overexpression, and KRAS G12A mutation. YCU-AML2 xenograft mice models developed AML and mimicked the clinical phenotype of the original patient. YCU-AML2 expressed high sensitivity to MEK inhibitors, such as trametinib and selumetinib. Moreover, YCU-AML2 also exhibited high sensitivity to L-asparaginase with glutaminase activity, perhaps because of its reliance on oxidative phosphorylation via glutaminolysis as its main energy source. We believe that the YCU-AML2 cell line and its xenograft model can serve as models to explore the molecular pathogenesis of high-risk AML with KMT2A::MLLT3 rearrangement, MECOM overexpression, and/or KRAS mutation and develop new treatment strategies., Competing Interests: Declarations. Conflict of interest: All authors declare no conflict of interests., (© 2025. The Author(s), under exclusive licence to Japanese Society of Hematology.)

Nucleophosmin (NPM1) is a nucleolar protein and one of the most frequently mutated genes in acute myeloid leukemia (AML). In addition to the commonly detected frameshift mutations in exon12 (NPM1c), previous studies have identified NPM1 gene rearrangements leading to the expression of NPM1-fusion proteins in pediatric AML. However, whether the NPM1-fusions are indeed oncogenic and how the NPM1-fusions cause AML have been largely unknown. In this study, we investigated the subcellular localization and leukemogenic potential of two rare NPM1-fusion proteins, NPM1::MLF1 and NPM1::CCDC28A. NPM1::MLF1 is present in both the nucleus and cytoplasm and occasionally induces AML in the mouse transplantation assay. NPM1::CCDC28A is more localized to the cytoplasm, immortalizes mouse bone marrow cells in vitro and efficiently induces AML in vivo. Mechanistically, both NPM1-fusions bind to the HOX gene cluster and, like NPM1c, cause aberrant upregulation of HOX genes in cooperation with XPO1. The XPO1 inhibitor selinexor suppressed HOX activation and colony formation driven by the NPM1-fusions. NPM1::CCDC28A cells were also sensitive to menin inhibition. Thus, our study provides experimental evidence that both NPM1::MLF1 and NPM1::CCDC28A are oncogenes with functions similar to NPM1c. Inhibition of XPO1 and menin may be a promising strategy for the NPM1-rearranged AML., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)