Acute myeloid leukemia-induced remodeling of the human bone marrow niche predicts clinical outcome

Blood cell production in the bone marrow is coordinated by specialized niches which are formed by mesenchymal stem and progenitor cells (MSPC) and their progeny. Using in vitro models, trephine biopsies and clinical data, I studied alterations of the bone marrow niche in human acute myeloid leukemia (AML).

MSPCs were found to be expanded in human AML, due to a loss of replicative quiescence. Their hematopoietic stem cell (HSC)-supporting capacity was decreased, as evidenced by abnormal expression of HSC-regulating genes and reduced peripheral blood cell counts. The differentiation capacity of MSPCs was also disturbed. Osteogenesis was inhibited when MSPCs and leukemic cells were cultured in direct cell contact. Inhibition was associated with abnormal gene expression, with particularly profound perturbation of the Wnt/ß-catenin pathway. Peripheral blood osteocalcin levels were abnormally low in AML patients, and the degree of osteocalcin reduction was correlated with long-term outcome. Leukemic bone marrow infiltration was associated with a sympathetic neuropathy, with very low levels of brain-derived neurotrophic factor and a trend towards decreased noradrenaline levels. 

These insights into the bone marrow microenvironment in human AML translate findings from preclinical models into the clinic. Whether progression of leukemia can be delayed by restoring the niche is unknown. We identified several candidates for treatment approaches targeting the bone marrow niche, such as the Wnt/ß-catenin pathway or the sympathetic nervous system. The ultimate goal of such therapies is eradication of leukemia-initiating cells leading cure of the affected patients.

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