Association between Dysfunction of the Nucleolar Stress Response and Multidrug Resistance in Pediatric Acute Lymphoblastic Leukemia

SIMPLE SUMMARY: Pediatric patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) relapse or are refractory to chemotherapy despite the low frequency of TP53 mutations. The nucleolar stress response is one of the mechanisms that activate P53 by ribosomal protein L11 (RPL11). We hypothesized that the lack of nucleolar stress response is related to chemoresistance and relapse in some pediatric BCP-ALL cases. We revealed that clinical BCP-ALL therapeutics, such as 6-mercaptopurine, methotrexate, daunorubicin, and cytarabine, induced the nucleolar stress response, and its treatment susceptibility was dependent on the nucleolar stress response. Furthermore, we observed decreased RPL11 expression at relapse in seven children with BCP-ALL in comparison to that at onset. Our findings provide new insights into the anti-leukemia mechanism in BCP-ALL and multidrug resistance and relapse via the nucleolar stress response, suggesting that the nucleolar stress response may be a potential therapeutic strategy to predict chemosensitivity and improve chemoresistance in pediatric BCP-ALL. ABSTRACT: Approximately 20% of pediatric patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) relapse or are refractory to chemotherapy despite the low frequency of TP53 mutations. The nucleolar stress response is a P53-activating mechanism via MDM2 inhibition by ribosomal protein L11 (RPL11). We analyzed the role of the nucleolar stress response using BCP-ALL cell lines and patient samples by drug sensitivity tests, Western blotting, and reverse transcription polymerase chain reaction. We revealed that the nucleolar stress response works properly in TP53 wild-type human BCP-ALL cell lines. Next, we found that 6-mercaptopurine, methotrexate, daunorubicin, and cytarabine had anti-leukemic effects via the nucleolar stress response within BCP-ALL treatment. Comparing the samples at onset and relapse in children with BCP-ALL, RPL11 mRNA expression decreased at relapse in seven of nine cases. Furthermore, leukemia cells with relapse acquired resistance to these four drugs and suppressed P53 and RPL11 expression. Our findings suggest that the nucleolar stress response is a novel anti-leukemia mechanism in BCP-ALL. As these four drugs are key therapeutics for BCP-ALL treatment, dysfunction of the nucleolar stress response may be related to clinical relapse or refractoriness. Nucleolar stress response may be a target to predict and improve the chemotherapy effect for pediatric BCP-ALL.