Exosome-driven lipolysis and bone marrow niche remodeling support leukemia expansion
Bijender Kumar, Marvin Orellana, Jamison Brooks, Srideshikan Sargur Madabushi, Paresh Vishwasrao, Liliana Echavarria Parra, James F. Sanchez, Amandeep Salhotra, Anthony S. Stein, Ching‐Cheng Chen, Guido Marcucci, Susanta Hui
Abstract
Since the bone marrow (BM) microenvironment and adipose tissue provide an attractive sanctuary for cancer progression and the acquisition of drug resistance phenotypes, 1-5 interactions between BM niche components and leukemia have recently attracted interest. However, the mechanisms underlying these complex interactions are not well understood. We previously reported that leukemic cells. through their secreted exosomes, induce microenvironment reprogramming to inhibit normal hematopoiesis and create a self-enforcing microenvironment for their own expansion. Here, using syngeneic acute myeloid leukemia (AML)/acute lymphoblastic leukemia (ALL) transplantation and knock-in leukemic mice models, we aimed to understand how leukemia remodels the BM niche. We describe a novel mechanism through which leukemic cells, via their exosomes, remodel BM niche subpopulations by enhancing the expression of adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) enzymes in adipocytes, resulting in increased lipolysis. Furthermore, pharmacological inhibition of ATGL and HSL rescued lipolysis, preserved adipocyte morphology and reduced fatty acid oxidation in leukemic cells. Finally, we show that leukemia progression can be delayed by increasing osteoblasts and adipocytes in vivo.