Regulating TKT activity inhibits proliferation of human acute lymphoblastic leukemia cells

Among pediatric blood cancers, acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy. Within ALL, T-cell acute lymphoblastic leukemia (T -ALL) accounts for 10 to 15% of all pediatric cases, and similar to 25% of adult cases. For T -ALL, its recurrence and relapse after treatment remain problematic. Therefore, it is necessary to develop new therapies for T -ALL. Recent studies suggested regulating energy metabolism is a novel approach to inhibit tumor growth, likely a promising treatment. Transketolase (TKT) is an important enzyme for modulating glucose metabolize in the pentose phosphate pathway (PPP). In this study, we treated T -ALL cells with different doses of niclosamide and primary T -ALL PBMCs were analyzed by RNA sequencing. T -ALL cells treated with niclosamide were analyzed with the Western blotting and TKT activity assay. Metabolism of T -ALL cells was evaluated by ATP assay and seahorse analyses. Lastly, we used a T -ALL xenograft murine model to determine effects of TKT knockdown on T -ALL tumor growth. Tumor samples were analyzed by H&E and IHC stainings. We found that niclosamide reduced T -ALL cell viability, and reduced expressions of TKT, Transketolase-Like Protein 1/2 (TKTL1/2) and transaldolase. In addition, niclosamide inhibited TKT enzyme activity, aerobic metabolism and glycolysis, finally leading to lower production of ATP. TKT knockdown inhibited tumor growth of xenograft T -ALL mice. Findings showed that niclosamide inhibits T -ALL cell growth by inhibiting TKT and energy metabolism.