Multi-Omic Analysis Reveals the Impact of Bortezomib in Hyperleukocytic Acute Myeloid Leukemia.

BACKGROUND

Hyperleukocytic acute myeloid leukemia (HL-AML) is associated with early complications and high mortality rates, highlighting the urgent need for more effective therapeutic strategies.

METHODS

This study conducted label-free proteomic analysis on serum from HL-AML and non-HL AML (NHL-AML) patients, integrating the data with the OHSU transcriptomic database. Flow cytometry was used to evaluate the in vitro impact of bortezomib. The in vivo effectiveness of bortezomib was assessed using the patient-derived xenograft (PDX) model of HL-AML.

RESULTS

Through integrated analysis of serum proteomics and transcriptomics, we observed an abnormal enrichment of the NF-kappa B pathway in HL-AML, suggesting its potential as a novel therapeutic target. Given that bortezomib is an inhibitor of the NF-kappa B pathway, HL-AML bone marrow cells were treated with varying concentrations of bortezomib (0, 5, 10, and 20 nM) in vitro. The results indicated a significant cytotoxic effect of bortezomib on HL-AML cells, accompanied by increased apoptosis rates and decreased proliferation. Co-administration of bortezomib with the frontline clinical chemotherapeutic regimen of daunorubicin and cytarabine (DA regimen) significantly extended mouse survival. Bone marrow immunophenotyping showed reductions in CD45 and CD33 cell populations, indicating disease amelioration. Immunohistochemical analysis further confirmed the inhibitory effect on the NF-kappa B pathway, as evidenced by reduced levels of P-IKBα and P-p65 proteins, validating the proposed therapeutic mechanism.

CONCLUSIONS

These data suggest that combination therapy involving bortezomib and the DA regimen may represent a promising strategy for HL-AML.