Knockdown of NPM1 and treatment with the NPM1 inhibitor NSC348884 both restored the sensitivity of KB cells to BTZ. Further analysis revealed that inhibition of NPM1 down-regulated CXCR4 expression at both transcriptional and translational level. In conclusion, NPM1 might causes BTZ resistance via up-regulating CXCR4 expression in MM and could be served as both a new prognostic biomarker and a promising therapeutic target.

Significantly, combining gemcitabine with NPM1 inhibitor NSC348884 synergistically suppresses CSN6-high pancreatic cancer xenografts. This study characterizes CSN6 as an oncogenic protein that promotes NPM1 stabilization by interacting with DCAF1, thereby enhancing ribosome biogenesis and cellular resistance to gemcitabine in PDAC. NPM1 may serve as a therapeutic target for CSN6 high PDAC that exhibits gemcitabine drug resistance.

GA was more frequent in NPM1wt AML and included ASXL1 (17.1% vs. 3.6%; p 0.0001), BCOR (7.5% vs. 1.6%; p < 0.0001), KMT2A (14.7% vs. 0.2%; p < 0.0001), RUNX1 (22.5% vs. 1.9%; p 0.0001), STAG2 (6.9% vs. 1.6%; p < 0.0001) and TP53 (19.1% vs. 4.1%; p < 0.0001). Mutations linked to therapy targets in AML, such as (FLT3 and IDH1/2), PTPN11, and DNMT3A (both associated with inferior outcomes), are more commonly observed in NPM1mut AML, whereas KMT2A, TP53, and myelodysplastic-related mutations are more commonly observed in NPM1wt AML.

Peptides were designed by introducing conservative mutations in the native 264-277 fragment and their structural features and amyloid propensities were assessed through ThT fluorescence, CD spectroscopies and SEM microscopy. Several "accelerator sequences" were employed in Amyloid Seeding Assays (ASAs): the sequence R1, with the single mutation Lys267/Arg, exhibited the greater ability to act as a promoter of the oligomerization of NPM1 264-277, limiting its toxicity and rescuing cell viability in OCI-AML3 cells.

Our results indicated that this mAb recognizes endogenous human NPM1 in several cancer cell lines and is suitable for immunoprecipitation, immunofluorescence staining, and immunoblotting. Therefore, mAb 4H7 is expected to be useful for the functional analysis of human NPM1 in cancer and for the diagnosis of malignant transformation via expression and localization assays.

In summary, high HIF-1α expression is potentially a baseline prognostic biomarker for poor RFS and cytarabine resistance in NPM1+FLT3-ITD- AML. Further studies with the large number of patients are warranted.

The evaluation of specific NPM1 genotypes identified AML patients with type D mutations being significantly associated with inferior outcomes, suggesting a reclassification of D cases to higher-risk groups.

Our findings contribute to a comprehensive characterization of NPM1-mutated AML, enhancing diagnostic accuracy and aiding in the detailed classification of the disease. This information may potentially guide targeted therapies or differentiation-based treatment strategies.

Our investigation confirmed that the morphological identification of CLB at diagnosis represents a reliable and easily reproducible tool for the early prediction of NPM1 mutations, enabling a streamlined genetic work-up for its confirmation. This may facilitate considering the early administration of individualized therapies by clinicians for specific patients.

Targeting NPM1 inhibits proliferation and induces apoptosis in hepatic progenitor cells and BEL-7402 cells, thus serving as a potential therapy for cHCC-CCA.