The Dynamic Evolution of Bone Marrow Adipocytes during Acute Lymphoblastic Leukemia Pathogenesis and Therapy

Background:The bone marrow microenvironment (BMM) undergo dynamic changes to physiological or pathological stimuli. Adipocytes are microenvironmental cell types that have a controversial role in ALL development. Rare studies have explicitly explored the BMM dynamics from ALL outset to treatment, especially the dynamic evolution of BM adipocytes. We sought to explore the dynamic evolution of bone marrow adipocytes during B-ALL pathogenesis and therapy.

Methods:Matched BM biopsies taken at initial ALL diagnosis and after treatment by gross histology in 46 adult ALL patients were compared. B-ALL patient-derived xenografts and invitro co-culture model were employed to investigate the dynamic changes of BM adipocytes and the impact of adipocytes on B-ALL development.

Results: At initial diagnosis, few of adipocytes cells were observed in BM of 46 adult ALL patients. After achieving remission, adipocytes sharply increased with decreasing leukemic cells. Consistently, treatment with dexamethasone and vincristine dramatically increased BM adipocytes in B-ALL patient-derived xenografts, which are consistent consistent with the finding observed in primary B-ALL patients. Furthermore, a significant decline of leukemic burden was observed in the Dex-pretreated mice in B-ALL PDX, together with an prolonged overall survival of B-ALL xenografts. This indicated that increased adipocytes in BM clearly suppressed the progression of B-ALL in xenografts. Adipocytes also inhibited in vitro ALL growth by apoptosis induction. Mechanistically, adipocytes inhibited the survival and expansion of B-ALL cells through a growth factors-dependent manner as well as secreting adiponectin.

Conclusions: Our results demonstrate the dynamical transition of BM adipocytic niche from disease to remission. Functionally, reestablishment of adipocyte BMM elicit a fate transform in ALL cells towards proliferation inhibition and apoptosis induction, which highlight the negative impact of adipocyte on the development of ALL.

Keywords: acute lymphoblastic leukemia, adipocyte, bone marrow microenvironment

No relevant conflicts of interest to declare.