Extracellular vesicles transfer chromatin-like structures that induce non-mutational dysfunction of p53 in bone marrow stem cells

Acute myeloid leukemia (AML) is the second most common leukemia. Despite the significant progress in AML therapy, little is known about how leukemia cells alter the bone marrow niche to facilitate their growth and evade chemotherapy or relapse after successful treatment. The tumor suppressor p53 has been highly expressed in the stem cells compartment, leading to high expression of p21 that induces cell cycle arrest required to maintain the stem cell property. We have identified a chromatin-like structure we termed EV-chromatin as a novel component of small EVs. EV-chromatin represents a mixture of DNA and proteins, such as histones and S100 proteins (S100A4, A8, A9, and A16). Interestingly, EV-chromatin isolated from leukemic blasts has the capacity to alter the proliferation of bone marrow mesenchymal stem cells (BM-MSCs). Mechanically, our data suggest that leukemic EV-chromatin downregulates the p53-mediated transcription of p21. This was accompanied by a significant increase in MDM2 levels, suggesting a p53-mediated decrease of p21, BAX, and PUMA. Conversely, treatment with the MDM-2 inhibitor Siremadlin rescued the p53 transcriptional activity in BM-MSCs.