ANP32B-mediated repression of p53 contributes to maintenance of normal and CML stem cells

Abstract Proper regulation of p53 signaling is critical for the maintenance of hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs). The hematopoietic cell-specific mechanisms regulating p53 activity remain largely unknown. Here, we demonstrate that conditional deletion of acidic leucine-rich nuclear phosphoprotein 32B (ANP32B) inhematopoieticcellsimpairs repopulation capacity and post-injury regeneration of HSCs.Mechanistically, ANP32B forms a repressive complex with and thus inhibitsthe transcriptional activity of p53 in hematopoietic cells, and p53 deletion rescues the functional defect in Anp32b-deficient HSCs. Of great interest, ANP32B is highly expressed in leukemic cells fromchronic myelogenous leukemia (CML) patients. Anp32b deletion enhances p53 transcriptional activity to impair LSCs function in a murine CML model, and exhibits synergistic therapeutic effects with tyrosine kinase inhibitors in inhibiting CML propagation. In summary, our findings provide a novel strategy to enhance p53 activity inLSCs by inhibiting ANP32B, and identify ANP32B as a potential therapeutic target in treating CML.