NPM1-fusion proteins promote myeloid leukemogenesis through XPO1-dependent HOX activation

Area of Science:

• Hematology
• Molecular Biology
• Oncology

Background:

• Nucleophosmin (NPM1) mutations are common in acute myeloid leukemia (AML).
• NPM1 gene rearrangements create NPM1-fusion proteins, particularly in pediatric AML.
• The oncogenic role and mechanisms of NPM1-fusions were previously unclear.

Purpose of the Study:

• To investigate the subcellular localization and leukemogenic potential of NPM1::MLF1 and NPM1::CCDC28A.
• To elucidate the molecular mechanisms by which these NPM1-fusions contribute to AML.
• To explore potential therapeutic targets for NPM1-rearranged AML.

Main Methods:

• Investigated subcellular localization of NPM1-fusion proteins.
• Utilized mouse transplantation assays to assess leukemogenic potential.
• Analyzed HOX gene cluster binding and upregulation.
• Assessed sensitivity to XPO1 and menin inhibitors.

Main Results:

• NPM1::MLF1 showed nuclear and cytoplasmic presence, occasionally inducing AML in mice.
• NPM1::CCDC28A localized primarily to the cytoplasm, immortalizing cells and efficiently inducing AML in vivo.
• Both NPM1-fusions aberrantly upregulated HOX genes by binding the HOX cluster with XPO1.
• XPO1 inhibition by selinexor suppressed HOX activation and colony formation.
• NPM1::CCDC28A-expressing cells were sensitive to menin inhibition.

Conclusions:

• NPM1::MLF1 and NPM1::CCDC28A function as oncogenes, similar to NPM1c.
• Aberrant HOX gene upregulation via XPO1 cooperation is a key mechanism.
• Targeting XPO1 and menin presents a promising therapeutic strategy for NPM1-rearranged AML.