Mutant P53 in pre-leukemic hematopoietic stem cells and the pathogenesis of Myelodysplastic Syndrome

Abstract

Myelodysplastic syndrome (MDS) is a clonal disease arising from mutated hematopoietic stem cells (HSCs). MDS stem cells originate from pre-leukemic HSCs, which have enhanced competitive advantage over wild-type (WT) HSCs but normal differentiation capacity. Recently, acquired somatic gain-of-function (GOF) TP53 mutations were identified in the blood of aged healthy individuals as well as in patients with MDS. However, the role of GOF TP53 mutations in clonal hematopoiesis and the pathogenesis of MDS is largely unknown. Based upon our previous studies and clinical findings, I hypothesized that GOF mutant p53 drives the development of pre-leukemic HSCs with enhanced competitive advantage, leading to clonal expansion and the pathogenesis of MDS. To test my hypothesis, I examined HSC behaviors in young p53+/+ and p53R248W/+ mice. I discovered that p53R248W enhances the repopulating potential of HSCs without affecting terminal differentiation. I also found that GOF mutant p53 protects HSCs from genotoxic stress and promotes their expansion. To investigate the role of mutant p53 in the pathogenesis of hematological malignancies, I monitored disease development in p53+/+ and p53R248W/+ mice and observed that some mutant p53 mice develop MDS during aging. Therefore, I demonstrated that GOF mutant p53 enhances the repopulating potential of HSCs and drives the development of pre-leukemic HSCs, predisposing aged mutant p53 mice to MDS development. Mechanistically, I found that mutant p53 increases the chromatin accessibility to genes important for HSC maintenance, including pluripotent gene Sox2 and chemokine gene Cxcl9. By performing biochemical experiments, I discovered that GOF mutant p53, but not WT p53, interacts with histone methyltransferase EZH2 and enhances histone H3 lysine 27 trimethylation (H3K27me3) at genes, including Mef/Elf4 and Gadd45g, that negatively regulate HSC self-renewal. Collectively, these findings demonstrated that GOF mutant p53 drives pre-leukemic HSC development through modulating epigenetic pathways. Thus, our studies have uncovered novel mechanistic and functional links between GOF mutant p53 and epigenetic regulators in pre-leukemic HSCs. This research may identify epigenetic regulator EZH2 as a novel target for the prevention and treatment of MDS patients with TP53 mutations.