NPM1 (Nucleophosmin 1)

Revumenib is a small-molecule inhibitor that selectively disrupts the menin-MLL interaction, and it is now in clinical use for treatment of MLLr and NPM1-mutated (NPM1c) acute leukemia...Immunocompromised mice engrafted with JUND-deficient leukemia cells exhibited reduced tumor burden compared to control mice engrafted with wild type leukemic cells. These findings reveal a role for JUND in MLLr AML and suggest that targeting JUND transcription factor activity enhances the efficacy of menin-MLL inhibitors towards MLLr leukemic cells.

Notably, the systemic delivery of chemically optimized siNPM1c via lipid nanoparticles (LNPs) significantly reduced leukemogenesis, and enhanced the therapeutic efficacy of the menin inhibitor revumenib and overcame its resistance in vivo...Targeting NPM1c with siRNA disrupts this interaction, reverses the oncogenic epigenetic landscape, and suppresses transcription. Our findings demonstrate that silencing NPM1c effectively suppresses AML by dismantling a pathogenic KAT7/p300-dependent acetylome, highlighting the potential of LNP‑delivered siNPM1c as a promising therapeutic strategy, either as a monotherapy or in combination with menin inhibition.

Transcriptomic analyses identified PIP5K1C as a downstream effector regulated through a competitive endogenous RNA mechanism in which circZBTB46 acts as a sponge to miR-25-3p, alleviating its repression of PIP5K1C. These findings uncover a previously unrecognized mechanism of drug resistance in ALK( + ) ALCL and establish circZBTB46 as a promising therapeutic target.

P3, N=302, Active, not recruiting, PETHEMA Foundation | Trial completion date: Jun 2025 --> Jul 2026

P2, N=300, Recruiting, Masonic Cancer Center, University of Minnesota | Trial completion date: Jun 2027 --> Jun 2028 | Trial primary completion date: Jun 2026 --> Jun 2027

P2, N=148, Not yet recruiting, Shen yang

CD244 drives immunomodulation via dysregulated CD8+T cell differentiation and cytokine secretion, positioning it as a prognostic biomarker and a promising target for immunotherapy in AML.

P=N/A, N=220, Recruiting, Gruppo Italiano Malattie EMatologiche dell'Adulto | Not yet recruiting --> Recruiting | Initiation date: Nov 2025 --> Jul 2026

Outcomes appear to be influenced by an interplay of disease context, clonal architecture, and therapeutic strategy rather than individual mutations alone, underscoring the need for integrated molecular profiling and prospective studies to guide management. This study highlights that MS with MR mutations may follow different cellular pathways to evolution.

Novel menin inhibitors, including revumenib, bleximenib, ziftomenib, and enzomenib, are currently under clinical evaluation, and selected updated clinical results were presented at the 2025 American Society of Hematology (ASH) Annual Meeting. This brief review summarizes the key findings and discusses the emerging clinical questions regarding combination strategies, treatment sequencing, and molecularly defined use of menin inhibitors.

Mutation-specific NPM1 IHC is a valuable tool for a rapid assessment of residual morphologic and molecular disease in mid- and postinduction NPM1mut AML.