Deciphering the Role of Bone Marrow Adipocytes in Pediatric Acute Myeloid Leukemia

Pediatric acute myeloid leukemia (AML) remains a life-threatening disease and relapses in pediatric patients still occur in 30-40% of cases. Despite the fact that intensive chemotherapy strategies are present and they show sustainable results, resistance to conventional therapies is still one the major problem of AML treatment. In recent years, the bone marrow microenvironment (BMM) arises as one of the key players for leukemia resistance with mesenchymal stromal cells (MSCs) recognized as key regulators. MSCs differentiation in bone marrow adipocytes (BMAs) remains poorly explored in the context of BMM and pediatric AML. This thesis aims to investigate the role of BMAs as active, AML-instructed components of the pediatric leukemic niche. We have used fully human two-dimensional and biomimetic three-dimensional co-culture models based on pediatric patient-derived MSCs and leukemic blasts, and we have investigated adipogenic differentiation and how adipocyte-rich environments influenced leukemic proliferation, metabolic adaptation, and response to chemotherapy. Results show that co-culture of BMAs with AML blasts promotes an enhanced mitochondrial activity, oxidative stress adaptation, and clonogenic potential in leukemic cells. In parallel, AML blasts induced adipocyte lipolysis, highlighting a bidirectional metabolic crosstalk within the niche. Additionally, while adipocyte-derived fatty acids support leukemic fitness and clonogenic output, they are not sufficient to fully sustain leukemic viability under strong therapeutic stress, indicating functional limits to niche-mediated protection. In conclusion, this work identifies BMAs as metabolically active components of the pediatric AML niche that enhance leukemic development and preserve clonogenic output, consistent with support of therapy-tolerant compartment. This suggests that targeting fatty acid transfer/utilization may help limit minimal residual disease and relapse.