The Expression and Activation of the NF-κB Pathway Correlate with Methotrexate Resistance and Cell Proliferation in Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Although its prognosis continually improves with time, a significant proportion of patients still relapse from disease because leukemia’s resistance to therapy. Methotrexate (MTX), folic-acid antagonist, chemotherapy agent commonly used against ALL and as an immune-system suppressant for rheumatoid arthritis that presents multiple complex mechanisms action resistance. Previous studies have shown MTX modulates nuclear factor kappa B (NF-κB) pathway, important family transcription factors involved in inflammation, immunity, cell survival, proliferation which are frequently hyperactivated ALL. Using gene set enrichment analysis publicly available expression data 161 newly diagnosed pediatric patients, we found Tumor necrosis α (TNF-α) signaling pathway via NF-κB be enriched Cancer Hallmark MTX-poor-responder patients. A transcriptomic using panel lines (six B-cell precursor acute seven T-cell leukemia) also identified same differentially among MTX-resistant lines, well slowly dividing cells. To better understand crosstalk between activity resistance, genetically modified express luciferase under NF-κB-binding-site promoter. We observed fold change triggered by TNF-α (but not MTX) treatment correlated across lines. At individual level, NFKB1 was directly associated poorer clinical response both increased TNF-α-triggered activation Despite these results, pharmacological inhibition (using BAY 11-7082 parthenolide) or stimulation exogenous supplementation) did alter significantly, evidencing interplay