Histidine re-sensitizes acute lymphoblastic leukemia cells to 6-mercaptopurine through tetrahydrofolate consumption and SIRT5-mediated desuccinylation

Given the progressive improvements in the efficacy of multiagent chemotherapy and the survival rate of pediatric acute lymphoblastic leukemia (ALL), concerted efforts are required to eradicate chemoresistance-induced disease progression and relapse. Our present study coupled chemoresistance in B-ALL with histidine metabolism deficiency. We provide evidence that histidine supplementation significantly shifts the 6-MP dose response in 6-MP-resistant B-ALL cell lines and xenograft mice model. Moreover, we prove that the THF consumption through histidine degradation pathway and SIRT5-mediated desuccinylation of HINT1 are required for the histidine combination therapy to promote B-ALL cells against 6-MP resistance. Collectively, our results demonstrated that histidine supplementation and SIRT5-HINT1 axis activators might be rational strategies to overcome chemoresistance, thus protect B-ALL patients from disease progression or recurrence. To provide insight into the genes that contribute to the response of leukemia cells to 6-MP and histidine, we performed RNA-seq in the Reh-6-MPR cells after treatment with vehicle, histidine, 6-MP, or both histidine and 6-MP.