Increased adipogenic potential of mesenchymal stromal cells from patients with acute myeloid leukemia inhibits normal hematopoiesis

Perivascular mesenchymal stem/stromal cells (MSCs) are key components of the healthy bone marrow hematopoietic niche, however, their role in supporting emergence and progression of acute myeloid leukemia (AML) is not well established. To gain further insight, we undertook an in-depth comparative study of human bone marrow MSCs derived from newly diagnosed AML patients and healthy donors. Our results demonstrated that, while maintaining normal morphology and viability, AML-derived MSCs possessed reduced proliferative and clonogenic capacity, decreased frequency of subendothelial quiescent MSCs and increased proportion of senescent cells. AML-derived MSCs had markedly increased adipogenic potential and delayed osteogenic differentiation. Functionally, adipo-biased vs. osteo-biased MSCs expressed increased levels of hematopoietic factors and induced increased proliferation, decreased quiescence and reduced in vitro hematopoietic colony forming capacity of CD34⁺ hematopoietic stem and progenitor cells (HSPCs). This comprehensive study of primary samples derived from AML patients demonstrated that AML bone marrow microenvironment is characterized by diminished stromal support, increased propensity toward adipogenesis, which depletes quiescent niches and negatively impacts normal hematopoiesis. Our findings highlight the importance of designing novel leukemia treatment aimed at normalizing bone marrow niche to better support normal hematopoiesis and prevent leukemia relapse. (author)