FTO inhibition represses B-cell acute lymphoblastic leukemia progression by inducing nucleolar stress and...

B-cell acute lymphoblastic leukemia (B-ALL) is a hematological malignancy characterized by the aberrant accumulation of malignant and immature B cells in the bone marrow. Recent reports including ours have demonstrated that RNA modifications play pivotal roles in B-ALL progression and drug resistance. In the current study, we show that fat mass and obesity-associated protein (FTO), a demethylase of N⁶-methyladenosine (m⁶A) RNA modifications, is highly expressed in relapsed or refractory (R/R) B-ALL patients and B-ALL cell lines. In human B-ALL cells, FTO knockdown inhibited proliferation and cell cycle progression in vitro, while FTO overexpression exhibited opposite effects. Moreover, FTO knockdown significantly attenuated tumorigenesis in vivo after transplantation into immune-compromised mice as shown by reduced tumor burden and extended mouse survival. Interestingly, our research suggested that FTO overexpression resulted in altered cytoplasmic and mitochondrial ribosome biogenesis, and FTO knockdown led to a nucleolar stress-like morphologic change and mitochondrial dysfunction in B-ALL cells. Mechanistically, we found that FTO upregulated the expression of a group of ribosomal proteins via m⁶A-modification, among which RPS15a, RPL9, MRPS16 and MRPL44 were the most prominent ones and confirmed at the mRNA and protein levels. FTO upregulates RPS15a, RPL9, MRPS16 and MRPL44 by mitigating YTHDF2-mediated m⁶A-mRNA decay. Comparatively, although FTO knockdown induced B-ALL cell apoptosis mildly, it synergized with Doxorubicin to promote apparent B-ALL cell death. Furthermore, we found that the FTO inhibitor FB23-2 combined with Doxorubicin markedly repressed B-ALL progression in vivo, accompanied by nucleolar stress-like changes and mitochondrial dysfunction. In summary, our data suggest that FTO is a critical RNA epigenetic promotor of B-ALL, and targeted FTO blockade synergizing with Doxorubicin could be a potential therapy for B-ALL, likely by inhibiting cytoplasmic and mitochondrial ribosome biogenesis.